4-(3-cyanophenyl)-6-pyridinylpyrimidine mglu5 modulators

ABSTRACT

The disclosures herein relate to novel compounds of formulawherein R1, R2, R3 and R4 and n are defined herein, and their use in treating, preventing, ameliorating, controlling or reducing the risk of inflammation, neurological or psychiatric disorders associated with modulating mGlu5 receptor function.

RELATED APPLICATION INFORMATION

This application is a continuation of U.S. patent application Ser. No.17/203,146, filed Mar. 16, 2021, which is a divisional of U.S. patentapplication Ser. No. 16/780,155, filed Feb. 3, 2020, now U.S. Pat. No.10,981,889, issued on Apr. 20, 2021, which is a continuation of U.S.patent application Ser. No. 16/280,512, filed Feb. 20, 2019, now U.S.Pat. No. 10,584,111, issued on Mar. 10, 2020, which is a continuation ofU.S. patent application Ser. No. 15/618,504, filed Jun. 9, 2017, nowU.S. Pat. No. 10,246,432, issued on Apr. 2, 2019, which is acontinuation of U.S. patent application Ser. No. 14/904,907, filed Jan.13, 2016, now U.S. Pat. No. 9,676,745, issued on Jun. 13, 2017 which isa 371 of International Patent Application PCT/GB2014/052184, filed Jul.17, 2014, which claims priority from GB Application No.: 1312800.4,filed Jul. 17, 2013. The entire contents of these applications areincorporated herein by reference in their entirety.

This application relates to novel compounds and their use as mGlu5modulators. Compounds described herein may be useful in the treatment orprevention of diseases in which glutamatergic neurotransmission isinvolved. The application is also directed to pharmaceuticalcompositions comprising these compounds and the manufacture and use ofthese compounds and compositions in the prevention or treatment of suchneuropathological diseases.

BACKGROUND OF THE INVENTION

Glutamate is the major excitatory neurotransmitter in the brain.Glutamate exerts its actions through both ionotropic and metabotropicglutamate receptors. There are eight metabotropic glutamate (mGlu)receptors belonging to the class C G protein-coupled receptor (GPCR)family. The eight mGlu receptors can be further divided into threegroups based on their sequence similarity, pharmacological profiles andtransduction mechanisms. The mGlu1 and mGlu5 receptors belong to groupI; these receptors are primarily located post-synaptically and couplethrough the G_(q/11) pathway. Group II is comprised of mGlu2 and mGlu3receptors and group III of mGlu4, mGlu6, mGlu7 and mGlu8 receptors; bothgroup II and group III receptors are located pre-synaptically andprimarily couple through G_(i/o). The mGlu receptors are composed ofthree distinct regions; the extracellular (Venus fly-trap domain),transmembrane and intracellular regions. Glutamate binds to theextracellular site. Modulators bind to the transmembrane domains wherethey can act to enhance (positive allosteric modulators or PAMs) ordecrease (negative allosteric modulators or NAMs) the activity ofglutamate. The mGlu receptors are involved in the fine tuning ofneuronal responses and changes in glutamatergic signalling have beenimplicated in a wide range of disease processes in humans and otherspecies (e.g. see Yasuhara and Chaki, The Open Medicinal ChemistryJournal, 2010, 4, 20-36). Thus modulating the activity of glutamatergicsignalling may be efficacious in the treatment of a variety ofneurological and psychiatric disorders.

The present invention relates to modulators of metabotropic glutamatereceptors, in particular the mGlu5 receptor. The mGlu5 receptor isabundant throughout the cortex, hippocampus, striatum, caudate nucleusand nucleus accumbens, areas involved in emotion, motivational processesand cognitive function. Compounds that act at the mGlu5 receptor haveutility in treating, preventing, ameliorating, controlling or reducingthe risk of multiple conditions; those of particular importance includeone or more of the following: dementia (including senile dementia anddementia caused by AIDS), pain (including headaches (such as migraineand cluster headaches), inflammatory pain (such as inflammatory tonguepain), visceral pain syndromes (such as painful bladder syndrome),gastro-intestinal pain (including irritable bowel syndrome), itch,fibromyalgia, disorders of the urinary tract (including incontinence,prostatitis, urinary frequency, nocturia, overactive bladder, cystitis,benign prostatic hyperplasia, detrusor hyperreflexia, outletobstruction, urinary urgency, pelvic hypersensitivity, urgeincontinence, urethritis, prostatodynia, idiopathic bladderhypersensitivity), substance-related disorders (including addiction,alcohol abuse, alcohol dependence, alcohol withdrawal, amphetaminedependence, amphetamine withdrawal, cocaine dependence, cocainewithdrawal, opioid dependence, opioid withdrawal), anxiety disorders(including agoraphobia, generalized anxiety disorder (GAD), obsessivecompulsive disorder (OCD), panic disorder, post-traumatic stressdisorders, social and specific phobias, substance-induced anxietydisorder), eating disorders (including obesity, anorexia and bulimia),attention-deficit/hyperactivity disorder (ADHD; ADD), deficits andabnormalities in attention and vigilance, executive functions andmemory, movement disorders (including Parkinson's disease,levodopa-induced dyskinesias, Tourette's syndrome, Huntington's disease,dystonias, restless leg syndrome, simple tics, complex tics andsymptomatic tics, periodic limb movement syndromes), amyotrophic lateralsclerosis (ALS), multiple sclerosis, schizophrenia, cancer (includingmelanoma, squamous cell carcinoma and astrocytoma), mood disorders(including major depressive disorder, dysthymia, treatment-resistantdepression and bipolar disorders I and II), rare neurological diseasesincluding inherited diseases and developmental disorders (includingautistic spectrum disorders [Asperger's syndrome, Rett's syndrome,Pervasive Development Disorder Not Otherwise Specified, ChildhoodDisintegrative Disorder] and Down's syndrome), fragile X syndrome andother areas of mental retardation, disorders of the gastro-intestinaltract (including gastroesophageal reflux disease, functional dyspepsia,functional heartburn, irritable bowel syndrome, functional bloating,functional diarrhoea, chronic constipation, post-operative ileus),epilepsy, retinopathy, neuroprotection (including Alzheimer's disease,stroke, status epilepticus and head injury), ischemias (includingcerebral ischameia especially acute ischemia, ischemic diseases of theeye), muscle spasms (such as local or general spasticity), autoimmunedisorders of the nervous system including paraneoplastic syndromes,spinal muscular atrophy, vomiting, skin disorders and any otherdisorders associated with irregularities of glutamatergic signaltransmission.

It has been suggested that the glutamatergic system is a mediator ofpsychiatric pathology and that, potentially, it is a common pathway fortherapeutic action of antidepressant medications (Sanacora et al.,Neuropharmacology, 2012, 62, 63-77). The mGlu5 receptor is located onGABAergic interneurones in the hippocampus and prefrontal cortex;inhibition of mGlu5 on these neurones may lead to the disinhibition ofintermediate interneurones, ultimately resulting in a decrease inglutamatergic transmission (Chaki et al., Neuropharmacology, 2012, 66,40-52). It has been shown that acute administration of an mGlu5 NAM(GRN-529) is efficacious in reducing depression (decreasing mobilitytime in tail suspension test and forced swim test), anxiety (byattenuation of stress-induced hyperthermia) and pain (reversal ofhyperalgesia due to sciatic nerve ligation) (Hughes et al.,Neuropharmacology, 2012, 66, 202-214). mGlu5 modulators may therefore beuseful in the treatment of depression, anxiety and other mood disordersand pain.

Activity of mGlu5 antagonists/NAMs as analgesics has been demonstratedin models of inflammatory pain. In the Complete Freund'sadjuvant-injected tongue (a model of inflammatory tongue pain) aselective mGlu5 antagonist significantly depressed mechanical allodyniaand heat hyperalgesia whilst continuous intrathecal administration of aselective mGlu5 agonist induced allodynia in naive rats (Liu et al.,Journal of Neuroinflammation, 2012, 9:258). NAMs and antagonists of themGlu5 receptor may have efficacy in reducing visceral pain syndromes.For example, in painful bladder syndrome (a type of visceral painsyndrome) the pharmacological activation of mGlu5 receptors in thecentral nucleus of the amygdala (a critical site for neuromodulation forprocessing of bladder nociception) has been shown to lead to increasethe response to bladder distension that drives bladder painsensitization (Crock et al., Journal of Neuroscience, 2012, 32,14217-14226). Glutamate receptors are distributed in pain relaystructures with glutamate having a key role in trigeminovascularactivation, central sensitization and cortical spreading depression(CSD); areas that are important for migraine and cluster headachepathophysiology (Monteith & Goadsby, Current Treatment Options inNeurology, 2011, 13, 1-14). A specific role of mGlu5 in centralsensitisation was demonstrated by the induction of long-termpotentiation in the superficial layer of the trigeminal nucleus caudalisby electrical stimulation of the mandibular nerve by the mGlu5 agonistCHPG which was selectively blocked by the mGlu5 NAM MPEP (Liang et al,Pain, 2005, 114, 417-428).

The mGlu5 receptor plays a critical role in behavioural responses tomultiple substances of abuse and may therefore have a role in thetreatment of substance abuse related disorders. The mGlu5 receptor islocated in brain regions thought to participate in reward-relatedbehaviours such as the bed nucleus of the stria terminalis. Acutepharmacological antagonism of the mGlu5 receptor has been shown todisrupt the reinforcing properties of, for example, pyschostimulants(e.g. cocaine; Grueter et al., The Journal of Neuroscience, 2008; 28,9261-9270), alcohol (Blednov and Harris, The International Journal ofNeuropsychopharmacology 2008, 11, 775-793) and nicotine (Palmatier etal., Neuropsychopharmacology 2008, 33, 2139-2147).

Benzodiazepines are generally regarded as effective anxiolytics butsuffer from dose-limiting side effects including sedation, memoryimpairment and abuse whilst selective-serotonin re-uptake inhibitorssuffer from long onset of action. The mGlu5 receptor is expressed inseveral brain regions associated with anxiety and may play a role intreatment of anxiety disorders. The mGlu5 NAM fenobam was demonstratedto have anxiolytic effects in multiple animal models (stress-inducedhyperthermia model, Vogel conflict test, Geller-Seifter conflict test,conditioned emotional response test) (Porter et al., The Journal ofPharmacology and Experimental Therapeutics, 2005, 315, 711-721). ThemGlu5 NAM fenobam also showed efficacy in phase II trials of generalizedanxiety disorder (GAD).

Proton spectroscopy has shown an increase in glutamatergic resonance inthe right prefrontal cortex and left striatum in attention deficithyperactivity disorder (ADHD) children compared to healthy controls,with the resonance in the prefrontal cortex correlating with age ofonset of ADHD symptoms (MacMaster et al, Biological Psychiatry, 2003,53, 184-187). Copy number variant association analysis in patients withADHD have shown variations in the gene encoding the mGlu5 receptor(GRM5) and other glutamatergic signalling pathway genes (Elia et al.,Molecular Psychiatry, 2010, 15, 637-646). This suggests that alterationin glutamatergic signalling via mGlu5 antagonism or negative allostericmodulation may be a treatment strategy for ADHD/ADD.

The substantia nigra is a key nucleus in the basal ganglia motor circuitplaying a key role in motor function. The mGlu5 receptor is involved indirect excitation of substantia nigra neurones which increase firingfrequency and burst-firing activity (Awad et al., Journal ofNeuroscience, 2001, 20, 7891-7879). The substantia nigra is the primarysite of pathology in a number of movement disorders includingParkinson's disease (PD), Tourette's and Huntington's disease. PD ischaracterised by the loss of dopamine producing neurones in thesubstantia nigra. Current treatments for PD include levodopa therapy tocounteract the loss of dopamine, although this treatment leads to thedevelopment of levodopa-induced dyskinesias (LID). There are two typesof dyskinesia, chorea (rapid uncontrolled movements) and dystonia (slowwrithing movements). The loss of dopaminergic neurones in the striatumcauses an increase in the glutamatergic output from the substantianigra. Antagonism of the mGlu5 receptor is clinically validated inreducing PD-LID, showing a clinically relevant and significantanti-dyskinetic effect without changing anti-parkisonian effects ofdopaminergic therapy and may be useful in the treatment of othermovement disorders. Antagonists or negative allosteric modulators ofmGlu5 also have the potential to treat anxiety and depression which arehigh co-morbidities in PD. Studies with the mGlu5 NAM dipraglurant showsefficacy in reversing both chorea and dystonias and dipraglurant isreported to be entering clinical trials as a treatment for other raredystonias.

In Huntington's disease and Tourette's syndrome there is a decrease inactivity in the substantia nigra hence agonists and PAMs of mGlu5 are ofinterest as therapeutic treatments in these disease settings. In a mousemodel of Huntington's disease mGlu5 PAMs were shown to beneuroprotective, protecting striatal neurones from excitotoxic celldeath (Doria et al., British Journal of Pharmacology, 2013, 169,909-921).

Positive allosteric modulators of the mGlu5 receptor may be useful intreatment of positive and negative symptoms of schizophrenia, and havebeen shown to have anti-psychotic effects in rat behavioural models(Kinney et al., The Journal of Pharmacology and ExperimentalTherapeutics, 2005, 313, 199-206). The mGlu5 receptor synergisticallyfacilitates NMDA receptor function and mGlu5 PAMs are in pre-clinicaltrials for the treatment of schizophrenia.

The mGlu5 receptor has been implicated in the growth and migration ofmany types of non-neuronal cancers including squamous cell carcinoma(Park et al., Oncology reports, 2007, 17, 81-87) and melanoma (Choi etal., PNAS, 2011, 108, 15219-15224) and therefore modulators of mGlu5 mayplay a role in the treatment of cancer.

Fragile X syndrome (FXS) is a monogenic disease that causes reduction inthe levels of fragile X mental retardation peptide 1 (Fmrp1). Fmrp1works in functional opposition to mGlu5; reduction in Fmrp1 leads toincreased mGlu5 signalling. There is good pre-clinical evidence that FXScan be modified by pharmacological intervention; in mouse models (Fmr1knock-out) symptoms and neuropathology of FXS can be rescued by mGlu5antagonism (Michalon et al., Neuron, 2012, 74, 49-56) and the mGlu5negative allosteric modulator (NAM) mavoglurant has been evaluated inphase III clinical trials for the treatment of FXS. FXS is the highestknown risk factor for developing autistic spectrum disorders. Under theDSM-IV classification autistic spectrum disorders (ASDs) include autism,Asperger's syndrome, Pervasive Developmental Disorder—Not OtherwiseSpecified, Rett's syndrome and childhood Disintegrative Disorder. ASDsare characterised by impairments in social interaction, communicationand language development and the presence of restricted interests orrepetitive behaviours. Hyperactivity in glutamatergic signalling hasbeen implicated in ASDs suggesting mGlu5 antagonism may betherapeutically beneficial for treatment of ASDs.

The most common neurological abnormality in FXS is epilepsy. There islong lasting functional enhancement of group I mGlu receptors in modelsof epilepsy such as the amygdala-kindled rat (Tang et al., CurrentNeuropharmacology, 2005, 3, 299-307). mGlu5 receptor negative allostericmodulators have been shown to block seizures in mouse models of epilepsy(Chapman et al., Neuropharmacology, 2000, 39, 1567-1574).

Gastroesophogeal reflux disease (GERD) is frequently caused by transientlower esophageal sphincter relaxation (TLESR), a mechanism thought to bepartly regulated by the mGlu5 receptor. A proof-of-concept trial showeda negative allosteric modulator of mGlu5 (ADX10059) had efficacy in thetreatment of GERD by significantly decreasing the time with pH<4throughout a 24 h period and reducing the number and duration ofsymptomatic reflux episodes (Keywood et al., Gut, 2009, 58, 1192-1199).

Selective blockade of the mGlu5 receptor potently protects culturedcortical neurones against NMDA or β-amyloid toxicity and also againstneurodegeneration in in vivo models (Bruno et al., Neuropharmacology2000, 39, 2223-2230). It is widely accepted that amyloid β contributesto the pathogenesis of Alzheimer's disease. The mGlu5 receptor has beenshown to be a co-receptor for amyloid β oligomers bound to cellularprion protein to activate the intracellular Fyn kinase (Um et al.,Neuron, 2013, 79, 887-902). Activation of the mGlu5 receptor removes therepressive effect of fragile X mental retardation peptide 1 on amyloidprecursor protein mRNA translation (a precursor to amyloid β) (Sokol etal., Neurology, 2011, 76, 1344-1352). The amyloid β-mediated impairmentof long term potentiation can be attenuated by co-treatment with mGlu5NAM MPEP (Wang et al., The Journal of Neuroscience, 2004, 24,3370-3378), suggesting that mGlu5 negative allosteric modulators mayplay a role in neuroprotection.

Amyotrophic lateral sclerosis (ALS; also known as motor neurone disease)is a neurological disorder characterised by motor neurone degeneration.Mutations in the superoxide dismutase 1 (SOD1) enzyme have been linkedto familial amyotrophic lateral sclerosis. The mGlu5 NAM MPEP has shownefficacy in a mouse model of ALS (hSOD1^(G93A)) with MPEP delayingdisease onset, increasing survival and slowing astrocytic degeneration(Rossi et al., Cell Death Differ. 2008, 15, 1691-1800). An up-regulationof mGlu5 expression is seen in ALS spinal cord compared to control(Aronica et al., Neuroscience, 2001, 105, 509-520).

SUMMARY OF THE INVENTION

Disclosed herein are novel compounds, and the first medical use of saidcompounds. The invention also relates to the first medical use of bothnovel and known compounds as negative allosteric modulators of mGlu5.

Compounds of the invention include compounds of formula (1)

where R₁ is halogen, optionally substituted C₁-C₃ alkyl, cyclopropyl,optionally substituted C₁-C₃ alkoxy, cyano, hydroxyl, nitro or NH₂;

R₂ is H or F;

X₁ and X₂ are CH or N, where one or both X₁ or X₂ is N; andQ is an optionally substituted 5 or 6 membered monocyclic aromaticheterocyclic group.Q may be an optionally substituted pyrazyl, pyridyl, oxazyl, thiazyl ordiazinyl.

Compounds may include compounds of formula 2

where R₁ is halogen, optionally substituted C₁-C₃ alkyl, cyclopropyl,optionally substituted C₁-C₃ alkoxy, cyano, hydroxyl, nitro or NH₂;

R₂ is H or F; and

Q is an optionally substituted pyridyl or pyrazyl group.

Compounds may include compounds of formula 3

where R₁ is halogen, optionally substituted C₁-C₃ alkyl, cyclopropyl,optionally substituted C₁-C₃ alkoxy, cyano, hydroxyl, nitro or NH₂;

R₂ is H or F;

R₃ is H, halogen, optionally substituted C₁-C₃ alkyl, optionallysubstituted C₁-C₃ alkoxy, cyano or a ring N;R₄ is H, halogen, optionally substituted C₁-C₃ alkyl, optionallysubstituted C₁-C₃ alkoxy, cyano or a ring N and n is 0-3.

Compounds may include compounds of formula 4

where R₁ is halogen, optionally substituted C₁-C₃ alkyl, cyclopropyl,optionally substituted C₁-C₃ alkoxy, cyano, hydroxyl, nitro or NH₂;

R₂ is H or F; and

R₃ is H, halogen, optionally substituted C₁-C₃ alkyl, optionallysubstituted C₁-C₃ alkoxy, cyano or a ring N;

Compounds may include compounds of formula 5

where R₁ is halogen, optionally substituted C₁-C₃ alkyl, cyclopropyl,optionally substituted C₁-C₃ alkoxy, cyano, hydroxyl, nitro or NH₂;

R₂ is H or F;

R₅ is H, D, halogen, optionally substituted C₁-C₃ alkyl or cyano; andR₆ is H, D, halogen, optionally substituted C₁-C₃ alkyl or cyano.

FIGURES

FIG. 1 shows a variety of synthetic routes to compounds of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to novel compounds. In the cases where compoundsare novel, the compounds themselves may be claimed. In cases where thecompounds have been synthesised previously, but no medical use has beenreported, the first medical use of known compounds may be claimed. Theinvention also relates to the use of both novel and known compounds asantagonists or negative allosteric modulators of mGlu5. The inventionfurther relates to the use of compounds in the manufacture ofmedicaments for use as mGlu5 receptor antagonists or negative allostericmodulators. The invention further relates to compounds, compositions andmedicaments for the treatment of dementia (including senile dementia anddementia caused by AIDS), pain (including headaches (such as migraineand cluster headaches), inflammatory pain (such as inflammatory tonguepain), visceral pain syndromes (such as painful bladder syndrome),gastro-intestinal pain (including irritable bowel syndrome), itch,fibromyalgia), disorders of the urinary tract (including incontinence,prostatitis, urinary frequency, nocturia, overactive bladder, cystitis,benign prostatic hyperplasia, detrusor hyperreflexia, outletobstruction, urinary urgency, pelvic hypersensitivity, urgeincontinence, urethritis, prostatodynia, idiopathic bladderhypersensitivity), substance-related disorders (including addiction,alcohol abuse, alcohol dependence, alcohol withdrawal, amphetaminedependence, amphetamine withdrawal, cocaine dependence, cocainewithdrawal, opioid dependence, opioid withdrawal), anxiety disorders(including agoraphobia, generalized anxiety disorder (GAD), obsessivecompulsive disorder (OCD), panic disorder, post-traumatic stressdisorders, social and specific phobias, substance-induced anxietydisorder), eating disorders (including obesity, anorexia and bulimia),attention-deficit/hyperactivity disorder (ADHD; ADD), deficits andabnormalties in attention and vigilance, executive functions and memory,movement disorders (including Parkinson's disease, levodopa-induceddyskinesias, Tourette's syndrome, Huntington's disease, dystonias,restless leg syndrome, simple tics, complex tics and symptomatic tics,periodic limb movement syndromes), amyotrophic lateral sclerosis (ALS),multiple sclerosis, schizophrenia, cancer (including melanoma, squamouscell carcinoma and astrocytoma), mood disorders (including majordepressive disorder, dysthymia, treatment-resistant depression andbipolar disorders I and II), rare neurological diseases includinginherited diseases and developmental disorders (including autisticspectrum disorders [Asperger's syndrome, Rett's syndrome, PervasiveDevelopment Disorder Not Otherwise Specified, Childhood DisintegrativeDisorder] and Down's syndrome), fragile X syndrome and other areas ofmental retardation, disorders of the gastro-intestinal tract (includinggastroesophageal reflux disease, functional dyspepsia, functionalheartburn, irritable bowel syndrome, functional bloating, functionaldiarrhoea, chronic constipation, post-operative ileus), epilepsy,retinopathy, neuroprotection (including Alzheimer's disease, stroke,status epilepticus and head injury), ischemias (including cerebralischameia especially acute ischemia, ischemic diseases of the eye),muscle spasms (such as local or general spasticity), autoimmunedisorders of the nervous system including paraneoplastic syndromes,spinal muscular atrophy, vomiting, skin disorders and any otherdisorders associated with irregularities of glutamatergic signaltransmission.

Compounds exemplified herein are based around the structure:

where R₁ is halogen, optionally substituted C₁-C₃ alkyl, cyclopropyl,optionally substituted C₁-C₃ alkoxy, cyano, hydroxyl, nitro or NH₂;

R₂ is H or F;

X₁ and X₂ are CH or N, where one or both X₁ or X₂ is N; andQ is an optionally substituted 5 or 6 membered monocyclic aromaticheterocyclic group.

Compounds may include compounds of formula 2

where R₁ is halogen, optionally substituted C₁-C₃ alkyl, cyclopropyl,optionally substituted C₁-C₃ alkoxy, cyano, hydroxyl, nitro or NH₂;

R₂ is H or F; and

Q is an optionally substituted pyridyl or pyrazyl group.

Compounds may include compounds of formula 3

where R₁ is halogen, optionally substituted C₁-C₃ alkyl, cyclopropyl,optionally substituted C₁-C₃ alkoxy, cyano, hydroxyl, nitro or NH₂;

R₂ is H or F;

R₃ is H, halogen, optionally substituted C₁-C₃ alkyl, optionallysubstituted C₁-C₃ alkoxy, cyano or a ring N;R₄ is H, halogen, optionally substituted C₁-C₃ alkyl, optionallysubstituted C₁-C₃ alkoxy, cyano or a ring N and n is 0-3. R₄ can be 1-3optional substituents, including ring nitrogen atoms. The furthersubstituents can be any position on the pyridyl ring.

Where n is greater than 1, each R₄ may be the same or different. Wherethe substituents are ring nitrogen atoms, n can be 1 or 2. Where thesubstituents are ring nitrogen atoms, the ring can be furthersubstituted with R₄ groups on different carbon atoms. Where R₄ is H andn is 3 (or n is 0, and hence R₄ is absent), the ring is not furthersubstituted, as formula 4.

Compounds may include compounds of formula 4

where R₁ is halogen, optionally substituted C₁-C₃ alkyl, cyclopropyl,optionally substituted C₁-C₃ alkoxy, cyano, hydroxyl, nitro or NH₂;

R₂ is H or F; and

R₃ is H, halogen, optionally substituted C₁-C₃ alkyl, optionallysubstituted C₁-C₃ alkoxy, cyano or a ring N.

Compounds may include compounds of formula 5

Where R₁ is halogen, optionally substituted C₁-C₃ alkyl, cyclopropyl,optionally substituted C₁-C₃ alkoxy, cyano, hydroxyl, nitro or NH₂;

R₂ is H or F;

R₅ is H, D, halogen, optionally substituted C₁-C₃ alkyl or cyano; andR₆ is H, D, halogen, optionally substituted C₁-C₃ alkyl or cyano.

Q can be an optionally substituted 5 or 6 membered monocyclic aromaticheterocyclic group. Q can be an aryl or heteroaryl group. In one generalembodiment, the substituents for the aryl and heteroaryl groups formingpart of Q may be selected from deutero, halo (fluoro, chloro, bromo oriodo), C₁₋₄ alkyl, C₁₋₄ alkylsulfanyl, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulphonyl, C₃₋₆ cycloalkyl, hydroxy, C₁₋₄ alkoxy, cyano, nitro,amino, C₁₋₄ alkylamino, C₂₋₄ alkenylamino, di-C₁₋₄ alkylamino, C₁₋₄acylamino, phenyl, phenylamino, benzoylamino, benzylamino, phenylamido,carboxy, C₁₋₄ alkoxycarbonyl or phenyl-C₁₋₁₀ alkoxycarbonyl, carbamoyl,mono-C₁₋₄ carbamoyl, di-C₁₋₄ carbamoyl or any of the above in which ahydrocarbyl moiety is itself substituted by halo, cyano, hydroxy, C₁₋₂alkoxy, amino, nitro, carbamoyl, carboxy or C₁₋₂ alkoxycarbonyl.

More particularly, the substituents for the aryl and heteroaryl groupsforming part of Q may be selected from deutero, halo (fluoro, chloro,bromo or iodo), C₁₋₄ alkyl, C₃₋₆ cycloalkyl, hydroxy, C₁₋₄ alkoxy,cyano, amino, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, C₁₋₄ acylamino,carboxy, C₁₋₄ alkoxycarbonyl, carbamoyl, mono-C₁₋₄ carbamoyl, di-C₁₋₄carbamoyl or any of the above substituents in which a hydrocarbyl moietyis itself substituted by halo, cyano, hydroxy, C₁₋₂ alkoxy, amino,nitro, carbamoyl, carboxy or C₁₋₂ alkoxycarbonyl.

In a particular embodiment, the substituents for the aryl and heteroarylgroups forming part of Q may be selected from deutero, fluoro, chloro,bromo, C₁₋₃ alkyl, C₃₋₆ cycloalkyl, hydroxy, C₁₋₄ alkoxy, cyano, amino,C₁₋₂ alkylamino, di-C₁₋₂ alkylamino, C₁₋₂ acylamino, carboxy, C₁₋₂alkoxycarbonyl, carbamoyl, mono-C₁₋₂ carbamoyl, di-C₁₋₂ carbamoyl or anyof the above substituents in which a hydrocarbyl moiety is itselfsubstituted by one or more fluorine atoms or by cyano, hydroxy, C₁₋₂alkoxy, amino, carbamoyl, carboxy or C₁₋₂ alkoxycarbonyl.

In a more particular embodiment, the substituents for the aryl andheteroaryl groups forming part of Q may be selected from deutero,fluoro, chloro, bromo, cyano, C₁₋₃ alkyl and C₁₋₃ alkoxy, wherein theC₁₋₃ alkyl and C₁₋₃ alkoxy moieties are each optionally substituted withone or more fluorine atoms.

The Q group may comprise a substituted aryl or heteroaryl group. In a6-membered aromatic ring the substituents may be located at the 2, 3, 4,5 or 6 positions. The aryl or heteroaryl group may comprise one, two,three, four or more substituents. The aryl group may be disubstituted,with the substitutions at any two of positions 2 to 6. The aryl groupmay be a 2,3-disubstituted, 2,4-disubstituted, 2,5-disubstituted,2,6-disubstituted, 3,4-disubstituted or 3,5-disubstituted aryl group.

The Q group may be a heteroaryl group, for example 2, 3 or 4 pyridyl.The heteroaryl group may optionally be further substituted, for example5-fluoro, 2-pyridyl or disubstituted, for example 4,5-difluoro,2-pyridyl. The heteroaryl group may be 5 or 6 membered, and contain oneor more heteroatoms. The heteroaryl group may be a 5 membered ringcontaining two or more heteroatoms. The heteroatoms may be independentlynitrogen, oxygen or sulphur.

Q may be an optionally substituted pyrazyl, pyridyl, oxazyl, thiazyl ordiazinyl. Q may be selected from optionally substituted rings of formula(a)

X₁ and X₂ can be CH or N. In particular examples, either X₁ or X₂ is N.In particular examples both X₁ and X₂ are N.

Where R₁ can be halogen, optionally substituted C₁-C₃ alkyl,cyclopropyl, optionally substituted C₁-C₃ alkoxy, cyano, hydroxyl, nitroor NH₂. R₁ is not H, and hence R₁ must be substituted with an atom otherthan H. R₁ can be F. R₁ can be Cl. R₁ can be methyl or substitutedmethyl, for example methoxymethyl, fluoromethyl, difluoromethyl ortrifluoromethyl. R₁ can be methoxy or substituted methoxy, for examplefluoromethoxy, difluoromethoxy or trifluoromethoxy. R₁ can be optionallysubstituted cyclopropyl. R₁ can be cyano. The optional substituents mayconsist of one or more halo, alkyl or alkoxy groups, or may be selectedfrom the list of optional substituents shown below.

R₂ can be H or F. R₂ can be H. R₂ can be F.

R₃ can be H, halogen, optionally substituted C₁-C₃ alkyl, optionallysubstituted C₁-C₃ alkoxy, cyano or a ring N. R₃ can be H. R₃ can be D.R₃ can be F. R₃ can be Cl. R₃ can be a ring nitrogen. R₃ can be methylor substituted methyl, for example methoxymethyl, fluoromethyl,difluoromethyl or trifluoromethyl. R₃ can be cyano. The optionalsubstituents may consist of one or more halo, alkyl or alkoxy groups, ormay be selected from the list of optional substituents shown below.

R₄ can be H, halogen, optionally substituted C₁-C₃ alkyl, optionallysubstituted C₁-C₃ alkoxy, cyano or a ring N. R₄ can be H. R₄ can be D.R₄ can be F. R₄ can be Cl. R₄ can be a ring nitrogen. R₄ can be methylor substituted methyl, for example methoxymethyl, fluoromethyl,difluoromethyl or trifluoromethyl. R₄ can be cyano. The optionalsubstituents may consist of one or more halo, alkyl or alkoxy groups, ormay be selected from the list of optional substituents shown below.

R₅ can be H, halogen, optionally substituted C₁-C₃ alkyl or cyano. R₅can be H. R₅ can be D. R₅ can be F. R₅ can be Cl. R₅ can be methyl orsubstituted methyl, for example methoxymethyl, fluoromethyl,difluoromethyl or trifluoromethyl. The optional substituents may consistof one or more halo, alkyl or alkoxy groups, or may be selected from thelist of optional substituents shown below.

R₆ can be H, halogen, optionally substituted C₁-C₃ alkyl or cyano. R₆can be H. R₆ can be D. R₆ can be F. R₆ can be Cl. R₆ can be methyl orsubstituted methyl, for example methoxymethyl, fluoromethyl,difluoromethyl or trifluoromethyl. The optional substituents may consistof one or more halo, alkyl or alkoxy groups, or may be selected from thelist of optional substituents shown below.

Any of the features of R₁-R₆, Q, X₁ and X₂ defined herein may becombined with any of the other features of R₁-R₆, Q, X₁ and X₂. Certainspecific examples of compounds are shown below.

Further embodiments of the invention include methods of treatmentcomprising administering a compound of formulas 1-5 as mGlu5 modulators.The treatment using a compound of formulas 1-5 may be in the treatmentof dementia (including senile dementia and dementia caused by AIDS),pain (including headaches (such as migraine and cluster headaches),inflammatory pain (such as inflammatory tongue pain), visceral painsyndromes (such as painful bladder syndrome), gastro-intestinal pain(including irritable bowel syndrome), itch, fibromyalgia), disorders ofthe urinary tract (including incontinence, prostatitis, urinaryfrequency, nocturia, overactive bladder, cystitis, benign prostatichyperplasia, detrusor hyperreflexia, outlet obstruction, urinaryurgency, pelvic hypersensitivity, urge incontinence, urethritis,prostatodynia, idiopathic bladder hypersensitivity), substance-relateddisorders (including addiction, alcohol abuse, alcohol dependence,alcohol withdrawal, amphetamine dependence, amphetamine withdrawal,cocaine dependence, cocaine withdrawal, opioid dependence, opioidwithdrawal), anxiety disorders (including agoraphobia, generalizedanxiety disorder (GAD), obsessive compulsive disorder (OCD), panicdisorder, post-traumatic stress disorders, social and specific phobias,substance-induced anxiety disorder), eating disorders (includingobesity, anorexia and bulimia), attention-deficit/hyperactivity disorder(ADHD; ADD), deficits and abnormalties in attention and vigilance,executive functions and memory, movement disorders (includingParkinson's disease, levodopa-induced dyskinesias, Tourette's syndrome,Huntington's disease, dystonias, restless leg syndrome, simple tics,complex tics and symptomatic tics, periodic limb movement syndromes),amnyotrophic lateral sclerosis (ALS), multiple sclerosis, schizophrenia,cancer (including melanoma, squamous cell carcinoma and astrocytoma),mood disorders (including major depressive disorder, dysthymia,treatment-resistant depression and bipolar disorders I and II), rareneurological diseases including inherited diseases and developmentaldisorders (including autistic spectrum disorders [Asperger's syndrome,Rett's syndrome, Pervasive Development Disorder Not Otherwise Specified,Childhood Disintegrative Disorder] and Down's syndrome), fragile Xsyndrome and other areas of mental retardation, disorders of thegastro-intestinal tract (including gastroesophageal reflux disease,functional dyspepsia, functional heartburn, irritable bowel syndrome,functional bloating, functional diarrhoea, chronic constipation,post-operative ileus), epilepsy, retinopathy, neuroprotection (includingAlzheimer's disease, stroke, status epilepticus and head injury),ischemias (including cerebral ischameia especially acute ischemia,ischemic diseases of the eye), muscle spasms (such as local or generalspasticity), autoimmune disorders of the nervous system includingparaneoplastic syndromes, spinal muscular atrophy, vomiting, skindisorders and any other disorders associated with irregularities ofglutamatergic signal transmission. The methods of treatment willtypically involve the administration of a therapeutically effectiveamount (preferably a non-toxic amount) of the compound to a subject(e.g. a mammalian subject such as a human) in need thereof.

Certain novel compounds of the invention show particularly highactivities as mGlu5 negative allosteric modulators; for example

-   3-chloro-4-fluoro-5-[6-(pyridin-2-yl)pyrimidin-4-yl]benzonitrile-   3-chloro-5-[6-(pyridin-2-yl)pyrimidin-4-yl]benzonitrile-   6-[6-(3-chloro-5-cyanophenyl)pyrimidin-4-yl]pyridine-3-carbonitrile-   3-methyl-5-[6-(pyridin-2-yl)pyrimidin-4-yl]benzonitrile-   3-chloro-5-[6-(pyridazin-3-yl)pyrimidin-4-yl]benzonitrile-   3-(4,4′-bipyrimidin-6-yl)-5-chlorobenzonitrile-   3-methyl-5-[6-(1H-pyrazol-1-yl)pyrimidin-4-yl]benzonitrile-   3-chloro-5-[6-(1H-pyrazol-1-yl)pyrimidin-4-yl]benzonitrile-   3-chloro-4-fluoro-5-[6-(1H-pyrazol-1-yl)pyrimidin-4-yl]benzonitrile-   3-chloro-4-fluoro-5-[4-(1H-pyrazol-1-yl)pyridin-2-yl]benzonitrile-   3-chloro-4-fluoro-5-[2-(1H-pyrazol-1-yl)pyridin-4-yl]benzonitrile-   3-chloro-4-fluoro-5-[6-(4-fluoro-1H-pyrazol-1-yl)pyrimidin-4-yl]benzonitrile-   3-methyl-5-{6-[(²H₃)-1H-pyrazol-1-yl]pyrimidin-4-yl}benzonitrile-   3-chloro-5-{6-[(²H₃)-1H-pyrazol-1-yl]pyrimidin-4-yl}benzonitrile-   3-chloro-4-fluoro-5-{6-[(²H₃)-1H-pyrazol-1-yl]pyrimidin-4-yl}benzonitrile-   3-(fluoromethyl)-5-[6-(1H-pyrazol-1-yl)pyrimidin-4-yl]benzonitrile-   3-chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile-   5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzene-1,3-dicarbonitrile-   3-chloro-5-[6-(5-methylpyridin-2-yl)pyrimidin-4-yl]benzonitrile-   3-chloro-5-[6-(5-chloropyridin-2-yl)pyrimidin-4-yl]benzonitrile-   5-[6-(pyridin-2-yl)pyrimidin-4-yl]benzene-1,3-dicarbonitrile-   3-chloro-4-fluoro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile-   3-methyl-5-[6-(5-methylpyridin-2-yl)pyrimidin-4-yl]benzonitrile-   3-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]-5-(methoxymethyl)benzonitrile-   3-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]-5-methoxybenzonitrile

To the extent that any of the compounds described have chiral centres,the present invention extends to all optical isomers of such compounds,whether in the form of racemates or resolved enantiomers. The inventiondescribed herein relates to all crystal forms, solvates and hydrates ofany of the disclosed compounds however so prepared. To the extent thatany of the compounds disclosed herein have acid or basic centres such ascarboxylates or amino groups, then all salt forms of said compounds areincluded herein. In the case of pharmaceutical uses, the salt should beseen as being a pharmaceutically acceptable salt.

Pharmaceutically acceptable salts that may be mentioned include acidaddition salts and base addition salts. Such salts may be formed byconventional means, for example by reaction of a free acid or a freebase form of a compound with one or more equivalents of an appropriateacid or base, optionally in a solvent, or in a medium in which the saltis insoluble, followed by removal of said solvent, or said medium, usingstandard techniques (e.g. in vacuo, by freeze-drying or by filtration).Salts may also be prepared by exchanging a counter-ion of a compound inthe form of a salt with another counter-ion, for example using asuitable ion exchange resin.

Examples of pharmaceutically acceptable salts include acid additionsalts derived from mineral acids and organic acids, and salts derivedfrom metals such as sodium, magnesium, or preferably, potassium andcalcium.

Examples of acid addition salts include acid addition salts formed withacetic, 2,2-dichloroacetic, adipic, alginic, aryl sulfonic acids (e.g.benzenesulfonic, naphthalene-2-sulfonic, naphthalene-1,5-disulfonic andp-toluenesulfonic), ascorbic (e.g. L-ascorbic), L-aspartic, benzoic,4-acetamidobenzoic, butanoic, (+)-camphoric, camphor-sulfonic,(+)-(1S)-camphor-10-sulfonic, capric, caproic, caprylic, cinnamic,citric, cyclamic, dodecylsulfuric, ethane-1,2-disulfonic,ethanesulfonic, 2-hydroxyethanesulfonic, formic, fumaric, galactaric,gentisic, glucoheptonic, gluconic (e.g. D-gluconic), glucuronic (e.g.D-glucuronic), glutamic (e.g. L-glutamic), α-oxoglutaric, glycolic,hippuric, hydrobromic, hydrochloric, hydriodic, isethionic, lactic (e.g.(+)-L-lactic and (±)-DL-lactic), lactobionic, maleic, malic (e.g.(−)-L-malic), malonic, (±)-DL-mandelic, metaphosphoric, methanesulfonic,1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic,palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, salicylic,4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic,tartaric (e.g. (+)-L-tartaric), thiocyanic, undecylenic and valericacids.

Particular examples of salts are salts derived from mineral acids suchas hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric andsulfuric acids; from organic acids, such as tartaric, acetic, citric,malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic,arylsulfonic acids; and from metals such as sodium, magnesium, orpreferably, potassium and calcium.

Also encompassed are any solvates of the compounds and their salts.Preferred solvates are solvates formed by the incorporation into thesolid state structure (e.g. crystal structure) of the compounds of theinvention of molecules of a non-toxic pharmaceutically acceptablesolvent (referred to below as the solvating solvent).

Examples of such solvents include water, alcohols (such as ethanol,isopropanol and butanol) and dimethylsulfoxide. Solvates can be preparedby recrystallising the compounds of the invention with a solvent ormixture of solvents containing the solvating solvent. Whether or not asolvate has been formed in any given instance can be determined bysubjecting crystals of the compound to analysis using well known andstandard techniques such as thermogravimetric analysis (TGE),differential scanning calorimetry (DSC) and X-ray crystallography.

The solvates can be stoichiometric or non-stoichiometric solvates.Particular solvates may be hydrates, and examples of hydrates includehemihydrates, monohydrates and dihydrates.

For a more detailed discussion of solvates and the methods used to makeand characterise them, see Bryn et al., Solid-State Chemistry of Drugs,Second Edition, published by SSCI, Inc of West Lafayette, Ind., USA,1999, ISBN 0-967-06710-3.

“Pharmaceutically functional derivatives” of compounds as defined hereinincludes ester derivatives and/or derivatives that have, or provide for,the same biological function and/or activity as any relevant compound ofthe invention. Thus, for the purposes of this invention, the term alsoincludes prodrugs of compounds as defined herein.

The term “prodrug” of a relevant compound includes any compound that,following oral or parenteral administration, is metabolised in vivo toform that compound in an experimentally-detectable amount, and within apredetermined time (e.g. within a dosing interval of between 6 and 24hours (i.e. once to four times daily)).

Prodrugs of compounds may be prepared by modifying functional groupspresent on the compound in such a way that the modifications arecleaved, in vivo when such prodrug is administered to a mammaliansubject. The modifications typically are achieved by synthesizing theparent compound with a prodrug substituent. Prodrugs include compoundswherein a hydroxyl, amino, sulfhydryl, carboxyl or carbonyl group in acompound is bonded to any group that may be cleaved in vivo toregenerate the free hydroxyl, amino, sulfhydryl, carboxyl or carbonylgroup, respectively.

Examples of prodrugs include, but are not limited to, esters andcarbamates of hydroxyl functional groups, ester groups of carboxylfunctional groups, N-acyl derivatives and N-Mannich bases. Generalinformation on prodrugs may be found e.g. in Bundegaard, H. “Design ofProdrugs” p. 1-92, Elsevier, New York-Oxford (1985).

Definitions

C₁-C₃ Alkyl

Alkyl means an aliphatic hydrocarbon group. The alkyl group may bestraight or branched. “Branched” means that at least one carbon branchpoint is present in the group, for example isopropyl. C₁-C₃ alkyl groupsinclude methyl, ethyl, n-propyl, i-propyl. The alkyl group may beoptionally substituted, e.g. as exemplified below.

The term alkyl also includes aliphatic hydrocarbon groups such asalkenyl, and alkylidene.

Alkenyl

Alkenyl means an unsaturated aliphatic hydrocarbon group. Theunsaturation may include one or more double bond, one or more triplebond or any combination thereof. The alkenyl group may be straight orbranched. “Branched” means that at least one carbon branch point ispresent in the group. Any double bond may, independently of any otherdouble bond in the group, be in either the (E) or the (Z) configuration.C₁-C₃ alkenyl groups include ethenyl, n-propenyl, i-propenyl. Wherealternative (E) and (Z) forms are possible, each is to be considered asindividually identified. The alkenyl group may be optionallysubstituted, e.g. as exemplified below.

Alkylidene

Alkylidene means any alkyl or alkenyl group linked to the remainder ofthe molecule via a double bond. The definitions and illustrationsprovided herein for alkyl and alkenyl groups apply with appropriatemodification also to alkylidene groups.

C₁-C₃ Alkoxy

Alkoxy means an aliphatic hydrocarbon group linked via an oxygen atom.The alkyl group may be straight or branched. “Branched” means that atleast one carbon branch point is present in the group, for exampleisopropyl. C₁-C₃ alkoxy groups include methoxy, ethoxy, n-propoxy,i-propoxy. The alkoxy group may be optionally substituted, e.g. asexemplified below.

Aryl

Aryl means any aromatic group in which all of the ring members arecarbon atoms, for example having 6 carbon atom ring members (phenyl).

Heteroaryl

Heteroaryl means an aromatic group in which at least one ring member isother than carbon. For example, at least one ring member (for exampleone, two or three ring members) may be selected from nitrogen, oxygenand sulphur. Exemplary heteroaryl groups include pyrazyl, pyridyl,oxazyl, thiazyl or diazinyl.

Optionally Substituted

“Optionally substituted” as applied to any group means that the saidgroup may if desired be substituted with one or more substituents, whichmay be the same or different. Examples of suitable substituents for“substituted” and “optionally substituted” moieties include halo(fluoro, chloro, bromo or iodo), deutero, C₁₋₃ alkyl, hydroxy, C₁₋₃alkoxy, cyano, amino, nitro, C₁₋₃ alkylamino, C₂₋₆ alkenylamino, di-C₁₋₃alkylamino, C₁₋₃ acylamino, di-C₁₋₃ acylamino, carboxy, C₁₋₃alkoxycarbonyl, carbamoyl, mono-C₁₋₃ carbamoyl, di-C₁₋₃ carbamoyl or anyof the above in which a hydrocarbyl moiety is itself substituted byhalo, cyano, hydroxy, C₁₋₂ alkoxy, amino, nitro, carbamoyl, carboxy orC₁₋₂ alkoxycarbonyl. In groups containing an oxygen atom such as hydroxyand alkoxy, the oxygen atom can be replaced with sulphur to make groupssuch as thio (SH) and thio-alkyl (S-alkyl). Optional substituentstherefore includes groups such as S-methyl. In thio-alkyl groups, thesulphur atom may be further oxidised to make a sulfoxide or sulfone, andthus optional substituents therefore includes groups such as S(O)-alkyland S(O)₂-alkyl.

Substituted groups thus include for example CN, CFH₂, CF₂H, CF₃, CH₂NH₂,CH₂OH, CH₂CN, CH₂SCH₃, CH₂OCH₃, OMe, OEt, Me, Et, —OCH₂O—, CO₂Me,C(O)Me, i-Pr, SCF₃, SO₂Me, NMe₂ etc. In the case of aryl groups, thesubstitutions may be in the form of rings from adjacent carbon atoms inthe aryl ring, for example cyclic acetals such as O—CH₂—O.

“Acyl” means an H—CO— or C₁₋₃ alkyl-CO— group wherein the alkyl group isas defined herein. Exemplary acyl groups include formyl, acetyl,propanoyl and 2-methylpropanoyl.

The term “pharmaceutical composition” in the context of this inventionmeans a composition comprising an active agent and comprisingadditionally one or more pharmaceutically acceptable carriers. Thecomposition may further contain ingredients selected from, for example,diluents, adjuvants, excipients, vehicles, preserving agents, fillers,disintegrating agents, wetting agents, emulsifying agents, suspendingagents, sweetening agents, flavouring agents, perfuming agents,antibacterial agents, antifungal agents, lubricating agents anddispersing agents, depending on the nature of the mode of administrationand dosage forms. The compositions may take the form, for example, oftablets, dragees, powders, elixirs, syrups, liquid preparationsincluding suspensions, sprays, inhalants, tablets, lozenges, emulsions,solutions, cachets, granules, capsules and suppositories, as well asliquid preparations for injections, including liposome preparations.

The dosages may be varied depending upon the requirements of thepatient, the severity of the condition being treated, and the compoundbeing employed. Determination of the proper dosage for a particularsituation is within the skill of the art. Generally, treatment isinitiated with the smaller dosages which are less than the optimum doseof the compound. Thereafter the dosage is increased by small incrementsuntil the optimum effect under the circumstances is reached. Forconvenience, the total daily dosage may be divided and administered inportions during the day if desired.

The magnitude of an effective dose of a compound will, of course, varywith the nature of the severity of the condition to be treated and withthe particular compound and its route of administration. The selectionof appropriate dosages is within the ability of one of ordinary skill inthis art, without undue burden. In general, the daily dose range may befrom about 10 μg to about 30 mg per kg body weight of a human andnon-human animal, preferably from about 50 μg to about 30 mg per kg ofbody weight of a human and non-human animal, for example from about 50μg to about 10 mg per kg of body weight of a human and non-human animal,for example from about 100 μg to about 30 mg per kg of body weight of ahuman and non-human animal, for example from about 100 μg to about 10 mgper kg of body weight of a human and non-human animal and mostpreferably from about 100 μg to about 1 mg per kg of body weight of ahuman and non-human animal.

Synthesis of Examples Preparation of the Compounds of the Invention

Compounds of the invention may be prepared by routes including those inFIG. 1, where in each case the starting aromatic or heteroaromatic ringmay be optionally substituted by groups in addition to those shown.Details of many of the standard transformations such as those in theroutes below and others which could be used to perform the sametransformations can be found in standard reference textbooks such as“Organic Synthesis”, M. B. Smith, McGraw-Hill (1994) or “AdvancedOrganic Chemistry”, 4^(th) edition, J. March, John Wiley & Sons (1992).

Heteroaryl trialkylstanannes, where the alkyl group is commonly methylor n-butyl, can be formed from the corresponding heteroaryl halide, forexample the bromide (for example as in Route 1, Step 1 or Route 4, whereheteroaryl trialkylstannanes can be synthesized for use in step 2).Conversion to the trialkylstannane can be performed under palladiummediated cross-coupling conditions, using a suitable palladium(0)catalyst, for example tetrakis(triphenylphosphine)palladium(0), in asuitable solvent such as DME, typically at an elevated temperature, forexample 80-110° C. Additionally a number of heteroaryl trilkylstannanesare available commercially. Cross-coupling of a heteroaryltrialkylstannane with a heteroaryl halide (for example in Route 1, Step2 or Route 4, Step 2), for example a chloropyrimidine, can be undertakenunder palladium mediated Stille cross-coupling conditions which will beknown to those skilled in the art. For example, Stille couplings can beundertaken using a suitable palladium(0) catalyst, for exampletetrakis(triphenylphosphine) palladium(0), a copper(I) salt, for examplecopper(I) iodide, in a suitable solvent such as toluene, typically at anelevated temperature, for example 110° C. An alternative to the use ofthe Stille cross-coupling procedure is the Negishi cross-couplingreaction (Negishi et al, J.C.S. Chem. Comm., 1977, 683-684) whichcouples an organozinc compound with an aryl halide or heteroaryl halide(for example in Route 5, Step 2), using a suitable palladium catalyst,for example tetrakis(triphenylphosphine) palladium(0), in a suitablesolvent such as THF, typically at an elevated temperature, for example50-60° C. Organozinc compounds can be prepared by methods which will beknown to those skilled in the art, for example by treatment of an arylhalide or heteroaryl halide with iso-propylmagnesium chloride in THF,followed by treatment with zinc(II) chloride.

Compounds may be prepared by reacting compounds of formula X:

where R₁ is halogen, optionally substituted C₁-C₃ alkyl, cyclopropyl,optionally substituted C₁-C₃ alkoxy, cyano, hydroxyl, nitro or NH₂; and

R₂ is H or F;

with a 2-pyridyl stannane reagent (Stille coupling) or 2-pyridylorganozinc reagent (Negishi coupling) to form an aryl-aryl bond.

Aryl or heteroarylboronic acids or esters, for example pinacol esters,can be used in the preparation of compounds of the invention, forexample in Route 1, Step 3; Route 2, Step 3; Route 3; Step 2, Route 4,Step 1 and Route 5, Step 1. Many aryl or heteroarylboronic acids oresters are commercially available. In addition, conditions which will beknown to those skilled in the art can be used for their synthesis. Forexample, halogen-lithium exchange, typically using an organolithiumreagent such as n-BuLi, can be used to form an aryl or heteroaryllithium nucelophile from an aryl or heteroarylhalide at low temperature,typically −78° C. in an inert solvent such as THF, which cansubsequently be reacted with a trialkylborate such as triisopropylborate to form an aryl or heteroarylboronic acid after aqueous workup.Aryl or heteroarylboronic pinacol esters can be formed directly fromaryl or heteroaryl compounds via iridium-catalysed C—H borylation usingmethods which are known to those skilled in the art, for example asreviewed by Hartwig et al, Chem. Rev. 2010, 110, 890-931. One suchmethod, for example as described in Steel et al, Org. Lett. 2009, 11,3586-3589, uses an iridium catalyst such as(1,5-cyclooctadiene)(methoxy) iridium(I) dimer, a ligand such as4,4′-di-tert-butyl-2,2′-dipyridyl and bis(pinacolato)diboron in asuitable solvent such as TBME, at a suitable temperature, for example80° C., under conventional or microwave heating conditions.Cross-coupling of an aryl or heteroarylboronic acid or ester with aheteroaryl halide, for example a chloropyrimidine, chloropyridine or abromopyridine, can be undertaken under palladium mediated Suzukicross-coupling conditions which will be known to those skilled in theart (for example in Route 1, Step 3; Route 2, Step 3; Route 3, Step 2 orRoute 4, Step 1). For example, Suzuki couplings can be undertaken usinga suitable palladium catalyst, for example[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) or thecomplex of this catalyst with dichloromethane, and a base, for examplecesium carbonate or sodium carbonate, in a suitable solvent or solventmixture, such as 1,4-dioxane or a mixture of 1,4-dioxane and water,typically at an elevated temperature, for example 80-100° C.

A number of heterocycle-substituted chloro- or bromopyrimidines orchloro- or bromopyridines are commercially available, for examplesIntermediates 34, 35 and 36. In addition, conditions which will be knownto those skilled in the art can be used for their synthesis. One suchmethod (for example Route 2) converts a heterocyclic carboxylic acid,via the acid chloride, to the corresponding beta ketoester using theanion of ethyl acetate. Subsequent condensation with formamidinehydrochloride under basic conditions, for example in the presence ofsodium methoxide in methanol at rt, can be used to form a hydroxylsubstituted pyrimidine, which can be converted to the chloropyrimidineunder standard conditions, for example using phosphorous(V) oxychloride.Other methods for the synthesis of heterocycle-substitutedchloropyrimidines or pyridines include those described above,palladium(0) catalysed Stille or Suzuki cross couplings. A furthermethod of the synthesis of a heterocycle-substituted chloropyrimidineuses the nucleophilic aromatic substitution reaction (SNAr) (for exampleRoute 3, Step 1). In the synthesis of compounds of the invention SNArreactions are typically conducted at 0° C. or rt, in a suitable solventsuch as DMF, and in the presence of a suitable base such as potassiumcarbonate.

General Procedures

Where no preparative routes are included, the relevant intermediate iscommercially available. Commercial reagents were utilized withoutfurther purification. Room temperature (rt) refers to approximately20-27° C. ¹H NMR spectra were recorded at 400 MHz on Bruker, Varian orJEOL instruments. Chemical shift values are expressed in parts permillion (ppm), i.e. (δ)-values. The following abbreviations are used forthe multiplicity of the NMR signals: s=singlet, br=broad, d=doublet,t=triplet, q=quartet, quin=quintet, h=heptet, dd=doublet of doublets,dt=double of triplets, m=multiplet. Coupling constants are listed as Jvalues, measured in Hz. NMR and mass spectroscopy results were correctedto account for background peaks. Chromatography refers to columnchromatography performed using 60-120 mesh silica gel and executed undernitrogen pressure (flash chromatography) conditions. TLC for monitoringreactions refers to TLC run using the specified mobile phase and silicagel F254 as a stationary phase from Merck. Microwave-mediated reactionswere performed in Biotage Initiator or CEM Discover microwave reactors.

LCMS experiments were carried out using electrospray conditions underthe following conditions. Instruments: Waters Alliance 2795, Waters 2996PDA detector, Micromass ZQ (or Hewlett Packard 1100 with G1315A DAD,Micromass ZQ for examples 24 and 25); Column: Waters X-Bridge C-18, 2.5micron, 2.1×20 mm or Phenomenex Gemini-NX C-18, 3 micron, 2.0×30 mm;Gradient [time (min)/solvent D in C (%)]:0.00/2, 0.10/2, 8.40/95,9.40/95; Solvents: solvent C=2.5 L H₂O+2.5 mL 28% ammonia in watersolution; solvent D=2.5 L MeCN+135 mL H₂O+2.5 mL 28% ammonia in watersolution); Injection volume 3 μL (or 1 μL for examples 24 and 25); UVdetection 230 to 400 nM; column temperature 45° C.; Flow rate 1.5 m/min.LCMS data in the experimental section are given in the format: Mass ion,retention time, approximate purity.

Abbreviations DMAC=N,N-dimethylacetamide

DME=1,2-dimethoxyethaneDMF=dimethylformamideDMSO=dimethylsulfoxideES=electrosprayEtOAc=ethyl acetateh=hour(s)HPβCD=(2-hydroxypropyl)-β-cyclodextrin

L=Litre

LC=liquid chromatographyLDA=lithium diisopropylamideMeCN=acetonitrilemin=minute(s)MS=mass spectrometryNMR=nuclear magnetic resonancert=room temperatureS_(N)Ar=nucleophilic aromatic substitution reactionTBME=tert-butyl methyl etherTHF=tetrahydrofuranTLC=thin layer chromatography

Prefixes n-, s-, i-, t- and tert- have their usual meanings: normal,secondary, iso, and tertiary.

Synthesis of Intermediates Route 1

Typical Procedure for the Preparation of Intermediates Via StilleCoupling of Commercially Available Trialkylstannanes with4,6-Dichloropyrimidine as Exemplified by the Preparation of Intermediate1, 4-Chloro-6-(Pyridin-2-Yl)Pyrimidine.

A mixture of 4,6-dichloropyrimidine (Intermediate 2, 1.2 g, 8.1 mmol)and 2-(tributylstannyl)pyridine (Intermediate 3, 3.0 g, 8.1 mmol) intoluene (10 mL) was degassed by purging with N₂ for 5 min.Tetrakis(triphenylphosphine)palladium(0) (940 mg, 0.81 mmol) andcopper(I) iodide (155 mg, 0.81 mmol) were added and the reaction mixturewas stirred at 110° C. for 16 h. After cooling to rt the reactionmixture was partitioned between H₂O (250 mL) and EtOAc (100 mL) and thephases were separated. The aqueous phase was extracted with EtOAc (2×100mL) and the combined organic phases were dried (Na₂SO₄) and concentratedin vacuo. Purification by gradient flash chromatography, eluting with0-10% EtOAc in hexane yielded the title compound (310 mg, 1.62 mmol) asa white solid.

Data in Table 1.

Typical Procedure for the Preparation of Intermediates Via Synthesis ofa Trialkylstannane from the Corresponding Heteroaryl Halide Followed byStille Coupling as Exemplified by the Preparation of Intermediate 4,6-(6-Chloropyrimidin-4-Yl)Pyridine-3-Carbonitrile.

A mixture of 2-bromo-5-cyanopyridine (Intermediate 5, 1.07 g, 5.85 mmol)and hexamethylditin (1.21 mL, 5.84 mmol) in DME (10 mL) was degassed bypurging with N₂ for 5 min. Tetrakis(triphenylphosphine)palladium(0) (330mg, 0.29 mmol) was added and the reaction mixture was stirred at 110° C.for 16 h before cooling to rt and partitioning between H₂O (50 mL) andEtOAc (25 mL). The phases were separated and the aqueous phase extractedwith EtOAc (2×25 mL). The combined organic phases were dried (Na₂SO₄)and concentrated in vacuo to yield crude6-(trimethylstannyl)nicotinonitrile (950 mg) as a brown liquid which wasused in the subsequent step without characterisation or furtherpurification.

4,6-Dichloropyrimidine (Intermediate 2, 500 mg, 3.36 mmol) and crude6-(trimethylstannyl)nicotinonitrile (895 mg) were dissolved in toluene(15 mL) and the reaction mixture was degassed by purging with N₂ for 5min. Tetrakis(triphenylphosphine)palladium(0) (388 mg, 0.34 mmol) andcopper iodide (64 mg, 0.33 mmol) were added and the reaction mixture wasstirred at 110° C. for 16 h. After cooling to rt, the reaction mixturewas partitioned between H₂O (50 mL) and EtOAc (25 mL), the phases wereseparated and the aqueous phase was extracted with EtOAc (2×25 mL). Thecombined organic phases were dried (Na₂SO₄) and concentrated in vacuo.Purification by gradient flash chromatography, eluting with 0-10% EtOAcin hexane yielded the title compound (175 mg, 0.81 mmol) as a lightyellow solid.

Data in Table 1. Intermediate 6, 3-(6-chloropyrimidin-4-yl)pyridazine

The title compound (250 mg, 1.30 mmol) was prepared in two steps from3-bromopyridazine (Intermediate 7, 500 mg, 3.14 mmol), hexabutylditin(1.23 mL, 2.43 mmol) and 4,6-dichloropyrimidine (Intermediate 2, 300 mg,2.01 mmol) using the methods of Intermediate 4.

Data in Table 1. Route 2

Typical Procedure for the Preparation of Intermediates Via PyrimidineRing Formation from Heteroaryl Carboxylic Acids as Exemplified by thePreparation of Intermediate 8, 6-Chloro-4,4′-Bipyrimidine.

4-Pyrimidinecarboxylic acid (Intermediate 9, 3.0 g, 24.2 mmol) in DMF(0.01 mL) and CH₂Cl₂ (60 mL) was cooled to 0° C. before the dropwiseaddition over 10 min of oxalyl chloride (2.7 mL, 31.5 mmol). Afterstirring at rt for 2 h the reaction mixture was concentrated in vacuoand the resulting crude acid chloride redissolved in THF (10 mL).Separately, EtOAc (8.3 mL, 84.6 mmol) was dissolved in THF (30 mL) andcooled to −78° C. before the dropwise addition of LDA (36.0 mL of a 2 Msolution in THF, 72.0 mmol). After stirring at −78° C. for 1 h the THFsolution of the crude acid chloride was added and the mixture stirred at−78° C. for 3 h. Aqueous HCl (1N, 25 mL) was added, followed by H₂O (100mL) and EtOAc (100 mL), and the phases were separated. The aqueous phasewas extracted with EtOAc (3×100 mL) and the combined organic phases weredried (Na₂SO₄) and concentrated in vacuo. Purification by gradient flashchromatography, eluting with 0-8% EtOAc in hexane yielded ethyl3-oxo-3-(pyrimidin-4-yl)propanoate (0.40 g, 2.06 mmol) as a white solid.

TLC: Rf 0.6, Hexane/Ethyl acetate 4:1

Ethyl 3-oxo-3-(pyrimidin-4-yl)propanoate (1.2 g, 6.18 mmol), sodiummethoxide (1.33 g, 24.6 mmol) and formamidine hydrochloride (1.0 g, 12.4mmol) were dissolved in MeOH (20 mL) and stirred at room temperature for24 h before concentration in vacuo. H₂O (50 mL) and EtOAc (50 mL) wereadded and the phases were separated. The aqueous phase was extractedwith EtOAc (3×50 mL) and the combined organic phases were dried(Na₂SO₄), and concentrated in vacuo to yield crude[4,4′-bipyrimidin]-6-ol (200 mg) which was used in the next step withoutfurther purification.

TLC: Rf 0.1, Ethyl acetate

Crude [4,4′-Bipyrimidin]-6-ol (120 mg, 0.69 mmol) was dissolved inphosphorus(V) oxychloride (4.0 mL, 42.9 mmol) and stirred at rt for 14h. The mixture was neutralized to approximately pH 7 with saturatedaqueous NaHCO₃ solution (30 mL) at 0° C. and stirred for 15 min beforethe addition of EtOAc (300 mL) and H₂O (100 mL). The phases wereseparated, the aqueous phase was extracted with EtOAc (300 mL), and thecombined organic phases were dried (Na₂SO₄) and concentrated in vacuo.Purification by gradient flash chromatography, eluting with 0-9% EtOAcin hexane yielded the title compound (42 mg, 0.22 mmol) as a whitesolid.

Data in Table 1. Route 3

Typical Procedure for the Preparation of Intermediates Via S_(N)Arreaction of a pyrazole with 4,6-dichloropyrimidine as exemplified by thepreparation of Intermediate 10,4-chloro-6-[(2H₃)-1H-pyrazol-1-yl]pyrimidine.

A mixture of 4,6-dichloropyrimidine (Intermediate 2, 1.50 g, 10.1 mmol),pyrazole-d₄ (Intermediate 11, 761 mg, 10.6 mmol) and K₂CO₃ (1.46 g, 10.6mmol) in DMF (10 mL) was stirred at rt for 17 h before adding to H₂O (50mL). After stirring for 5 min the title compound (1.20 g, 6.54 mmol) wasisolated by filtration as a pale yellow solid.

Data in Table 1.

Intermediate 12, 4-chloro-6-(4-fluoro-1H-pyrazol-1-yl)pyrimidine.

The title compound (622 mg, 3.13 mmol) was prepared from4-fluoropyrazole (Intermediate 13, 551 mg, 6.40 mmol),4,6-dichloropyrimidine (Intermediate 2, 908 mg, 4.57 mmol) and K₂CO₃(884 mg, 6.40 mmol) in DMF (20 mL) using the methods of Intermediate 10.

Data in Table 1. Routes 4 and 5

Typical Procedure for the Preparation of Intermediates Via SuzukiCoupling of Boronic Acids or Esters with 4,6-Dichloropyrimidine asExemplified by the Preparation of Intermediate 14,3-(6-Chloropyrimidin-4-Yl)-5-Fluorobenzonitrile.

4,6-Dichloropyrimidine (Intermediate 2, 1.8 g, 12.2 mmol),3-cyano-5-fluorophenylboronic acid (Intermediate 15, 2.0 g, 12.1 mmol)and cesium carbonate (7.8 g, 23.9 mmol) were dissolved in1,4-dioxane/water (9:1, 10 mL) and the mixture was degassed by purgingwith N₂ for 5 min.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (490 mg, 0.60 mmol) was added and the reactionmixture was stirred at 90° C. for 16 h. The reaction mixture waspartitioned between H₂O (250 mL) and EtOAc (150 mL), the phases wereseparated and the aqueous phase extracted with EtOAc (2×150 mL). Thecombined organic phases were dried (Na₂SO₄) and concentrated in vacuo.Purification by gradient flash chromatography, eluting with 0-10% EtOAcin hexane yielded the title compound (1.0 g, 4.28 mmol) as a whitesolid.

Data in Table 1. Intermediate 16,3-chloro-5-(6-chloropyrimidin-4-yl)-4-fluorobenzonitrile

The title compound (110 mg, 0.41 mmol) was prepared from3-chloro-5-cyano-2-fluorophenylboronic acid, pinacol ester (Intermediate17, 245 mg, 0.87 mmol) and 4,6-dichloropyrimidine (Intermediate 2, 200mg, 1.34 mmol) using the methods of Intermediate 14.

Data in Table 1. Intermediate 18,3-chloro-5-(6-chloropyrimidin-4-yl)benzonitrile

The title compound (4.0 g, 16.0 mmol) was prepared from3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(Intermediate 19, 17.6 g, 66.8 mmol) and 4,6-dichloropyrimidine(Intermediate 2, 9.0 g, 60.4 mmol) using the methods of Intermediate 14.

Data in Table 1. Preparation of intermediate 19,3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

The title compound was prepared from 3-chlorobenzonitrile (Intermediate20, 1.23 g, 8.94 mmol), (1,5-cyclooctadiene)(methoxy)iridium(I) dimer(89 mg, 0.13 mmol), 4,4′-di-tert-butyl-2,2′-dipyridyl (72 mg, 0.27 mmol)and bis(pinacolato)diboron (2.49 g, 9.81 mmol) in TBME (24 mL) using themethods of Intermediate 28, step 2. Purification by gradient flashchromatography, eluting with 0-10% diethyl ether in isohexane yieldedthe title compound (1.39 g, 5.27 mmol) as a clear oil.

Data in Table 1. Intermediate 21,3-(6-chloropyrimidin-4-yl)-5-methylbenzonitrile

The title compound (170 mg, 0.74 mmol) was prepared from3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(Intermediate 22, 326 mg, 1.34 mmol) and 4,6-dichloropyrimidine(Intermediate 2, 200 mg, 1.34 mmol) using the methods of Intermediate14.

Data in Table 1. Preparation of intermediate 22,3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

The title compound was prepared from 3-methylbenzonitrile (Intermediate23, 1.76 mL, 15.0 mmol), (1,5-cyclooctadiene)(methoxy)iridium(I) dimer(149 mg, 0.23 mmol), 4,4′-di-tert-butyl-2,2′-dipyridyl (121 mg, 0.45mmol) and bis(pinacolato)diboron (4.19 g, 16.5 mmol) in TBME (30 mL)using the methods of Intermediate 28, step 2. Purification by gradientflash chromatography, eluting with 0-10% diethyl ether in isohexaneyielded the title compound (2.34 g, 9.63 mmol) as a white solid.

Data in Table 1. Preparation of intermediate 38,3-(methoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

The title compound was prepared from 3-(methoxymethyl)benzonitrile(Intermediate 37, 221 mg, 15.0 mmol),(1,5-cyclooctadiene)(methoxy)iridium(I) dimer (14 mg, 0.02 mmol),4,4′-di-tert-butyl-2,2′-dipyridyl (12 mg, 0.05 mmol) andbis(pinacolato)diboron (419 mg, 1.65 mmol) in TBME (5 mL) at 80° C. for1 h using microwave irradiation using the methods of Intermediate 28,step 2. Purification by gradient flash chromatography, eluting with 0-8%ethyl acetate in hexane yielded the title compound (285 mg, 1.04 mmol)as a white solid.

Data in Table 1. Intermediate 39,3-(6-chloropyrimidin-4-yl)-5-(methoxymethyl)benzonitrile

The title compound (300 mg, 1.16 mmol) was prepared from3-(methoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(Intermediate 38, 549 mg, 2.01 mmol) and 4,6-dichloropyrimidine(Intermediate 2, 272 mg, 1.83 mmol) using the methods of Intermediate14.

Data in Table 1. Intermediate 41,3-(6-chloropyrimidin-4-yl)-5-methoxybenzonitrile

The title compound (3.2 g, 13.2 mmol) was prepared from3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(Intermediate 40, 5.1 g, 19.7 mmol) and 4,6-dichloropyrimidine(Intermediate 2, 2.7 g, 18.1 mmol) using the methods of Intermediate 14.

Data in Table 1.

Typical Procedure for the Preparation of Intermediates Via Ir-CatalysedBoronic Ester Formation and Subsequent Suzuki Coupling with4,6-Dichloropyrimidine as Exemplified by the Preparation of Intermediate24, 5-(6-Chloropyrimidin-4-Yl)Benzene-1,3-Dicarbonitrile.

Under N₂, a solution of (1,5-cyclooctadiene)(methoxy)iridium(I) dimer(505 mg, 0.76 mmol), 4,4′-di-tert-butyl-2,2′-dipyridyl (409 mg, 1.52mmol) and bis(pinacolato)diboron (13.4 g, 52.7 mmol) in TBME (135 mL)was prepared. A portion of this solution (15 mL) was added toisophthalonitrile (Intermediate 25, 700 mg, 5.46 mmol) and the mixtureheated for 1 h at 80° C. in a microwave reactor. The reaction wasrepeated 8 more times on this scale and the combined reaction mixtureswere concentrated in vacuo. Purification by gradient flashchromatography, eluting with 0-10% EtOAc in hexane yielded5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isophthalonitrile (5.6 g,22.0 mmol).

TLC: Rf 0.3, Hexane/Ethyl acetate 4:1

¹H NMR: (400 MHz, DMSO-d₆) δ: 1.33 (s, 12H), 8.25-8.27 (m, 2H),8.60-8.61 (m, 1H)

4,6-Dichloropyrimidine (Intermediate 2, 3.28 g, 22.0 mol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isophthalonitrile (5.6 g,22.0 mmol) and cesium carbonate (14.4 g, 44.2 mmol) were dissolved in1,4-dioxane/water (9:1, 60 mL) and the mixture was degassed by purgingwith N₂ for 10 min.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (806 mg,1.10 mmol) was added and the reaction mixture was stirred at 90° C. for3 h. After cooling to rt the reaction mixture was partitioned betweenH₂O (250 mL) and EtOAc (150 mL), the phases were separated and theaqueous phase was extracted with EtOAc (2×150 mL). The combined organicphases were dried (Na₂SO₄) and concentrated in vacuo. Purification bygradient flash chromatography, eluting with 0-15% EtOAc in hexaneyielded the title compound (1.70 g, 7.06 mmol) as a white solid.

Data in Table 1. Preparation of Further Boronic Acid and Boronic EsterIntermediates Preparation of intermediate 26,(3-cyano-5-methylphenyl)boronic Acid

3-Bromo-5-methylbenzonitrile (Intermediate 27, 250 mg, 1.28 mmol) wasdissolved in THF (5 mL), cooled to −78° C. and n-BuLi (1.19 mL of a 1.6M solution in THF, 1.91 mmol) was added dropwise. After stirring at −78°C. for 30 min triisopropyl borate (0.64 mL, 2.81 mmol) was addeddropwise at −78° C., the cooling bath was removed and the reactionmixture was stirred at rt for 16 h. Saturated aqueous ammonium chloridesolution (50 mL) and EtOAc (25 mL) were added and the phases wereseparated. The aqueous phase was extracted with EtOAc (2×25 mL), thecombined organic phases were dried (Na₂SO₄) and concentrated in vacuo toyield the crude title compound (200 mg) as an off-white solid which wasused without further purification.

Data in Table 1. Preparation of intermediate 28,3-(fluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

(Diethylamino)sulfur trifluoride (2.01 mL, 2.0 mmol) was added to asolution of 3-(hydroxymethyl)benzonitrile (Intermediate 29, 1.0 g, 7.50mmol) in CH₂Cl₂ (50 mL) and the resulting mixture was stirred at rt for2 h. Saturated aqueous NaHCO₃ solution (30 mL) and CH₂Cl₂ (20 mL) wereadded and the phases were separated. The aqueous phase was extractedwith CH₂Cl₂ (2×25 mL) and the combined organic phases were dried(Na₂SO₄) and concentrated in vacuo. Purification by gradient flashchromatography, eluting with 0-25% EtOAc in hexane yielded3-(fluoromethyl)benzonitrile (500 mg, 3.70 mmol).

¹H NMR: (400 MHz, CDCl₃) δ: 5.45 (d, J=47, 2H), 7.53-7.57 (m, 1H),7.62-7.70 (m, 3H)

A mixture of 3-(fluoromethyl)benzonitrile (500 mg, 3.70 mmol),(1,5-cyclooctadiene) (methoxy)iridium(I) dimer (74 mg, 0.11 mmol),4,4′-di-tert-butyl-2,2′-dipyridyl (60 mg, 0.22 mmol) andbis(pinacolato)diboron (1.1 g, 4.06 mmol) were dissolved in TBME (15mL). The reaction mixture was heated at 80° C. for 16 h under N₂ beforecooling to rt and partitioning between H₂O (50 mL) and EtOAc (25 mL).The aqueous phase was extracted with EtOAc (2×25 mL), the combinedorganic phases were dried (Na₂SO₄) and concentrated in vacuo.Purification by gradient flash chromatography, eluting with 0-80% EtOAcin hexane yielded crude3-(fluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(Intermediate 28, 950 mg) which was used in the subsequent step withoutcharacterisation or further purification.

TABLE 1 Intermediate Name Data 1 4-chloro-6-(pyridin-2-yl)pyrimidineLCMS: m/z 192.2 (M + H)+ (ES+), at 2.94 min, 98% ¹H NMR: (400 MHz,DMSO-d₆) δ: 7.65 (ddd, J = 7.6, 4.8, 1.1, 1H), 8.08 (td, J = 7.8, 1.8,1H), 8.41-8.49 (m, 2H), 8.79-8.85 (m, 1H), 9.19 (d, J = 1.2, 1 H) 24,6-dichloropyrimidine Commercially available, CAS 1193-21-1 32-(tributylstannyl)pyridine Commercially available, CAS 17997-47-6 46-(6-chloropyrimidin-4-yl)pyridine- ¹H NMR: (400 MHz, DMSO-d₆)3-carbonitrile δ: 8.47 (d, J = 1.2, 1H), 8.60 (d, J = 1.5, 2H),9.25-9.29 (m, 2H) 5 2-bromo-5-cyanopyridine Commercially available, CAS139585-70-9 6 3-(6-chloropyrimidin-4-yl)pyridazine TLC: Rf 0.3,Hexane/Ethyl acetate 4:1 7 3-bromopyridazine Commercially available, CAS88491-61-6 8 6-chloro-4,4′-bipyrimidine ¹H NMR: (400 MHz, DMSO-d₆) δ:8.43 (dd, J = 5.2, 1.2, 1H), 8.49 (d, J = 1.2, 1H), 9.13 (d, J = 4.9,1H), 9.29 (d, J = 0.9, 1H), 9.45 (d, J = 1.2, 1H) 94-pyrimidinecarboxylic acid Commercially available, CAS 31462-59-6 104-chloro-6-[(²H₃)-1H- ¹H NMR: (400 MHz, CDCl₃) pyrazol-1-yl]pyrimidineδ: 7.96 (s, 1H), 8.78 (s, 1H) 11 pyrazole-d₄ Commercially available, CAS53013-62-0 12 4-chloro-6-(4-fluoro-1H- ¹H NMR: (400 MHz, CDCl₃)pyrazol-1-yl)pyrimidine δ: 7.70 (d, J = 3.9, 1H), 7.94 (d, J = 0.8, 1H),8.40 (d, J = 3.9, 1H), 8.79 (s, 1H) 13 4-fluoropyrazole Commerciallyavailable, CAS 35277-02-2 14 3-(6-chloropyrimidin-4-yl)- LCMS: m/z notobserved 5-fluorobenzonitrile (ES+), at 3.89 min, 95% ¹H NMR: (400 MHz,DMSO-d₆) δ: 8.12-8.18 (m, 1H), 8.42-8.47 (m, 1H), 8.55 (d, J = 0.9, 1H),8.61 (t, J = 1.4, 1H), 9.19 (d, J = 1.2, 1H) 153-cyano-5-fluorophenylboronic Commercially available, CAS acid304858-67-1 16 3-chloro-5-(6-chloropyrimidin- ¹H NMR: (400 MHz, DMSO-d₆)4-yl)-4-fluorobenzonitrile δ: 8.21 (s, 1H), 8.43-8.48 (m, 1H), 8.51-8.58(m, 1H), 9.26 (d, J = 1.2, 1H) 17 3-chloro-5-cyano-2- Commerciallyavailable, CAS fluorophenylboronic 1218790-15-8 acid, pinacol ester 183-chloro-5-(6-chloropyrimidin- LCMS: m/z not observed 4-yl)benzonitrile(ES+), at 3.91 min, 95% ¹H NMR: (400 MHz, DMSO-d₆) δ: 8.27 (s, 1H), 8.53(s, 1H), 8.59 (s, 1H), 8.66 (s, 1H), 9.16 (s, 1H) 193-chloro-5-(4,4,5,5-tetramethyl- ¹H NMR: (400 MHz, CDCl₃)1,3,2-dioxaborolan-2-yl)benzonitrile δ: 1.35 (s, 12H), 7.69-7.70 (m,1H), 7.96-7.98 (m, 2H) 20 3-chlorobenzonitrile Commercially available,CAS 766-84-7 21 3-(6-chloropyrimidin-4-yl)- ¹H NMR: (400 MHz, DMSO-d₆)5-methylbenzonitrile δ: 2.47 (s, 3H), 7.91-7.94 (m, 1H), 8.43-8.54 (m,3H), 9.16 (d, J = 0.9, 1H) 22 3-methyl-5-(4,4,5,5-tetramethyl- ¹H NMR:(400 MHz, CDCl₃) 1,3,2-dioxaborolan-2-yl)benzonitrile δ: 1.35 (s, 12H),2.38 (s, 3H), 7.52 (s, 1H), 7.82 (s, 1H), 7.89 (s, 1H) 233-methylbenzonitrile Commercially available, CAS 620-22-4 245-(6-chloropyrimidin-4-yl)benzene- ¹H NMR: (400 MHz, DMSO-d₆)1,3-dicarbonitrile δ: 8.60 (d, J = 1.2, 1H), 8.70-8.74 (m, 1H), 9.00 (d,J = 1.5, 2H), 9.22 (d, J = 0.9, 1H) 25 isophthalonitrile Commerciallyavailable, CAS 626-17-5 26 (3-cyano-5-methylphenyl)boronic TLC: Rf 0.3,Hexane/Ethyl acid acetate 1:1 27 3-bromo-5-methylbenzonitrileCommercially available, CAS 124289-21-0 28 3-(fluoromethyl)-5-(4,4,5,5-— tetramethyl-1,3,2-dioxaborolan- 2-yl)benzonitrile 293-(hydroxymethyl)benzonitrile Commercially available, CAS 874-97-5 302-bromo-5-fluoropyridine Commercially available, CAS 41404-58-4 315-methyl-2-(tributylstannyl)pyridine Commercially available, CAS189195-41-3 32 5-chloro-2-(tributylstannyl)pyridine Commerciallyavailable, CAS 611168-63-9 33 5-methyl-2-(tributylstannyl)pyridineCommercially available, CAS 189195-41-3 344-chloro-6-(1H-pyrazol-1-yl)pyrimidine Commercially available, CAS114833-95-3 35 2-chloro-4-(1H-pyrazol-1-yl)pyridine Commerciallyavailable, CAS 1209459-70-0 36 4-bromo-2-(1H-pyrazol-1-yl)pyridineCommercially available, CAS 1159814-68-2 373-(methoxymethyl)benzonitrile Commercially available, CAS 1515-86-2 383-(methoxymethyl)-5-(4,4,5,5- ¹H NMR: (400 MHz, DMSO-d₆)tetramethyl-1,3,2-dioxaborolan- δ: 1.31 (s, 12H), 3.31 (s,2-yl)benzonitrile. 3H), 4.48 (s, 2H), 7.88-7.94 (m, 3H) 393-(6-chloropyrimidin-4-yl)-5- ¹H NMR: (400 MHz, DMSO-d₆)(methoxymethyl)benzonitrile δ: 3.36 (s, 3H), 4.57 (s, 2H), 7.98-8.00 (m,1H), 8.50-8.55 (m, 2H), 8.63-8.66 (m, 1H), 9.16 (d, J = 0.9, 1H) 403-methoxy-5-(4,4,5,5-tetramethyl-1,3,2- Commercially available, CASdioxaborolan-2-yl)benzonitrile 1035266-33-1 413-(6-chloropyrimidin-4-yl)-5- ¹H NMR: (400 MHz, DMSO-d₆)methoxybenzonitrile δ: 3.92 (s, 3H), 7.68-7.71 (m, 1H), 8.10 (dd, J =2.4, 1.5, 1H), 8.27-8.30 (m, 1H), 8.52 (d, J = 1.2, 1H), 9.16 (d, J =1.2, 1H)

Synthesis of Examples Route 1

Typical Procedure for the Preparation of Examples Via Suzuki Couplingwith a Commercially Available or Synthesized Boronic Acid or BoronicEster as Exemplified by the Preparation of Example 1,3-Chloro-4-Fluoro-5-[6-(Pyridin-2-Yl)Pyrimidin-4-Yl]Benzonitrile

A mixture of 4-chloro-6-(pyridin-2-yl)pyrimidine (Intermediate 1, 96 mg,0.50 mmol), 3-chloro-5-cyano-2-fluorophenylboronic acid, pinacol ester(Intermediate 17, 169 mg, 0.60 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (22 mg, 0.03mmol) and 1 M aqueous Na₂CO₃ solution (1.25 mL, 1.25 mmol) in1,4-dioxane (1.2 mL) was degassed by purging with N₂ for 5 min beforeheating at 80° C. for 2 h. After cooling to rt and concentration invacuo CH₂Cl₂ and H₂O were added and the phases were separated. Theaqueous phase was extracted with CH₂Cl₂ and the combined organic phaseswere concentrated in vacuo. Purification by gradient flashchromatography, eluting with 10-30% EtOAc in isohexane followed bytrituration with diethyl ether yielded the title compound (35 mg, 0.11mmol) as a white solid.

Data in Table 2. Typical Procedure for the Preparation of Examples ViaIr-Catalysed Synthesis of a Boronic Ester Followed by Suzuki Coupling asExemplified by the Preparation of Example 2,3-Chloro-5-[6-(Pyridin-2-Yl)Pyrimidin-4-Yl]Benzonitrile.

A mixture of 3-chlorobenzonitrile (Intermediate 20, 1.0 g, 7.3 mmol),(1,5-cyclooctadiene)(methoxy)iridium(I) dimer (144 mg, 0.22 mmol),4,4′-di-tert-butyl-2,2′-dipyridyl (117 mg, 0.44 mmol) andbis(pinacolato)diboron (2.0 g, 7.88 mmol) were dissolved in TBME (15mL). The reaction mixture was heated at 80° C. for 16 h under N₂ beforecooling to rt and partitioning between H₂O (50 mL) and EtOAc (25 mL).The aqueous phase was extracted with EtOAc (2×25 mL), the combinedorganic phases were dried (Na₂SO₄) and concentrated in vacuo.Purification by gradient flash chromatography, eluting with 0-80% EtOAcin hexane yielded crude3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(1.90 g) which was used in the subsequent step without characterisationor further purification.

A mixture of 4-chloro-6-(pyridin-2-yl)pyrimidine (Intermediate 1) (200mg, 1.04 mmol), crude3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(275 mg) and cesium carbonate (678 mg, 2.08 mmol) were dissolved indioxane/water (9:1, 10 mL) and the mixture was degassed by purging withN₂ for 5 min.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (42.6 mg, 0.05 mmol) was added and the reactionmixture was stirred at 90° C. for 16 h. After cooling to rt the reactionmixture was partitioned between H₂O (50 mL) and EtOAc (25 mL), theaqueous phase was extracted with EtOAc (2×25 mL) and the combinedorganic phases dried (Na₂SO₄). After concentration in vacuo purificationby gradient flash chromatography, eluting with 0-30% EtOAc in hexaneyielded the title compound (45 mg, 0.15 mmol) as a light yellow solid.

Data in Table 2. Route 2 Example 6,3-(4,4′-bipyrimidin-6-yl)-5-chlorobenzonitrile

The title compound (27 mg, 0.09 mmol) was prepared from6-chloro-4,4′-bipyrimidine (Intermediate 8, 40 mg, 0.21 mmol) and crude3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (50mg) at 100° C. using the methods of Example 2,3-chloro-5-[6-(pyridin-2-yl)pyrimidin-4-yl]benzonitrile.

Data in Table 2. Route 3

Typical Procedure for the Preparation of Examples Via Suzuki Couplingwith a Commercially Available or Synthesized Boronic Acid or BoronicEster as Exemplified by the Preparation of Example 7,3-Methyl-5-[6-(1H-Pyrazol-1-Yl)Pyrimidin-4-Yl]Benzonitrile

The title compound (27 mg, 0.10 mmol) was prepared from4-chloro-6-(1H-pyrazol-1-yl)pyrimidine (Intermediate 34, 225 mg, 1.25mmol) and (3-cyano-5-methylphenyl)boronic acid (Intermediate 26, 200 mg,1.24 mmol) at 90° C. using the methods of Example 2,3-chloro-5-[6-(pyridin-2-yl)pyrimidin-4-yl]benzonitrile.

Data in Table 2. Route 4

Typical Procedure for the Preparation of Examples Via Synthesis of aTrialkylstannane where not Commercially Available, Followed by StilleCoupling as Exemplified by the Preparation of Example 17,3-Chloro-5-[6-(5-Fluoropyridin-2-Yl)Pyrimidin-4-Yl]Benzonitrile.

A mixture of 2-bromo-5-fluoropyridine (Intermediate 30, 500 mg, 2.89mmol) and hexamethylditin (946 mg, 2.89 mmol) in DME (10 mL) wasdegassed by purging with N₂ for 5 min before the addition oftetrakis(triphenylphosphine)palladium(0) (166 mg, 0.14 mmol). Thereaction mixture was stirred at 110° C. for 16 h before cooling to rtand partitioning between H₂O (50 mL) and EtOAc (25 mL). The phases wereseparated and the aqueous phase was extracted with EtOAc (2×25 mL). Thecombined organic phases were dried (Na₂SO₄) and concentrated in vacuo toyield crude 5-fluoro-2-(trimethylstannyl)pyridine (700 mg) which wasused in the subsequent step without characterisation or furtherpurification.

3-chloro-5-(6-chloropyrimidin-4-yl)benzonitrile (Intermediate 18, 100mg, 0.39 mmol) and crude 5-fluoro-2-(trimethylstannyl)pyridine (114 mg)were dissolved in toluene (15 mL) and the reaction mixture was degassedby purging with N₂ for 5 min before the addition oftetrakis(triphenylphosphine)palladium(0) (46.2 mg, 0.04 mmol) andcopper(I) iodide (7.6 mg, 0.03 mmol). The reaction mixture was stirredat 110° C. for 16 h before cooling to rt and partitioning between H₂O(50 mL) and EtOAc (25 mL). The phases were separated and the aqueousphase was extracted with EtOAc (2×25 mL). The combined organic phaseswere dried (Na₂SO₄) and concentrated in vacuo. Purification by gradientflash chromatography, eluting with 0-10% EtOAc in hexane yielded thetitle compound (37 mg, 0.12 mmol) as a pale yellow solid.

Data in Table 2. Route 5 Typical Procedure for the Preparation ofExamples Via Negishi Coupling as Exemplified by the Preparation ofExample 17,3-Chloro-5-[6-(5-Fluoropyridin-2-Yl)Pyrimidin-4-Yl]Benzonitrile.

To a dried flask under nitrogen was added i-PrMgCl (2M in THF, 11.2 mL,22.4 mmol) and 2-bromo-5-fluoropyridine (Intermediate 30, 3.94 g, 22.4mmol) in THF (40 mL). After stirring at rt for 3.5 h ZnCl₂ (0.5 M inTHF, 51.2 mL, 25.6 mmol) was added dropwise maintaining the temperaturebelow 25° C. and the mixture was stirred for a further 1 h. Separately,under nitrogen to a solution of3-chloro-5-(6-chloropyrimidin-4-yl)benzonitrile (Intermediate 18, 4.00g, 16.0 mmol) in THF (80 mL) was addedtetrakis(triphenylphosphine)palladium (924 mg, 0.80 mmol) and thepreviously prepared zincate solution was then added dropwise and themixture was heated to 50-60° C. for 18 h. After cooling to rt themixture was evaporated to approximately 10% of its original volume,diluted with EtOAc (400 mL) and washed with water (500 mL). The aqueousphase was then extracted with EtOAc (3×400 mL) and the combined organicphases were washed with brine (500 mL), dried (anhydrous Na₂SO₄),filtered and concentrated in vacuo. Purification by flashchromatography, eluting with 5% EtOAc in hexane yielded the titlecompound (2.97 g, 9.56 mmol) as a white solid. The purified compound wascombined with product batches from other reactions (17.6 g totalmaterial) and re-crystallised from hot EtOAc to yield the title compound(12.5 g, 40.2 mmol) as a white solid.

Data in Table 2.

TABLE 2 Ex Synthetic No. Name Intermediates route ¹H NMR LCMS data 13-chloro-4-fluoro-5-[6-(pyridin-2-  1, 17 1 (400 MHz, CDCl₃) δ: ppm7.43-7.54 m/z not observed yl)pyrimidin-4-yl]benzonitrile (m, 1H)7.84-7.94 (m, 2H) 8.47 (dd, (ES⁺), at 4.32 J = 6.1, 2.1, 1H) 8.56 (d, J= min, 100% 7.8, 1H) 8.76 (d, J = 3.9, 1H) 8.93 (d, J = 0.8, 1H) 9.40(d, J = 1.2, 1H) 2 3-chloro-5-[6-(pyridin-2-  1, 20 1 (400 MHz, DMSO-d₆)δ: 7.66 (ddd, m/z not observed yl)pyrimidin-4-yl]benzonitrile J = 7.6,4.8, 1.2, 1H), 8.09 (ES⁺), at 4.33 (td, J = 7.8, 1.8, 1H), 8.30 min,100% (dd, J = 2.0, 1.4, 1H), 8.52 (dt, J = 7.9, 0.9, 1H), 8.61-8.72 (m,1H), 8.77 (t, J = 1.5, 1H), 8.80-8.89 (m, 1H), 9.01 (d, J = 1.2, 1H),9.45 (d, J = 1.5, 1H) 3 6-[6-(3-chloro-5-cyanophenyl)pyrimidin-  4, 20 1(400 MHz, CDCl₃) δ: 7.83-7.86 m/z not observed4-yl]pyridine-3-carbonitrile (m, 1H) 8.22 (dd, J = 8.2, (ES⁺), at 4.522.1 Hz, 1H) 8.46-8.53 (m, 2H) 8.76 min, 100% (d, J = 8.2, 1H) 8.89 (d, J= 1.5, 1H) 9.04-9.09 (m, 1H) 9.44 (d, J = 1.2, 1H) 43-methyl-5-[6-(pyridin-2-  1, 26 1 (400 MHz, CDCl₃) δ: ppm 2.55 m/z273.1 yl)pyrimidin-4-yl]benzonitrile (s, 3H), 7.50 (dd, J = 6.4, (M +H)⁺ (ES⁺), at 4.9, 1H), 7.64 (d, J = 0.6, 4.03 min, 100% 1H), 7.93-7.98(m, 1H), 8.31 (s, 1H), 8.38 (s, 1H), 8.59 (d, J = 7.6, 1H), 8.81 (d, J =4.0, 1H), 8.87 (d, J = 0.9, 1H), 9.38 (d, J = 1.2, 1H) 53-chloro-5-[6-(pyridazin-3-  6, 20 1 (400 MHz, CDCl₃) δ: ppm 7.75-7.84m/z not observed yl)pyrimidin-4-yl]benzonitrile (m, 2H), 8.51-8.53 (m,2H), 8.70-8.74 (ES⁺), at 3.42 (m, 1H), 9.16 (d, J = 1.2, 1H), min, 100%9.37-9.40 (m, 1H), 9.45 (d, J = 1.5, 1H) 6 3-(4,4′-bipyrimidin-6-yl)-5- 8, 20 2 (400 MHz, CDCl₃) δ: ppm 7.82-7.85 m/z not observedchlorobenzonitrile (m, 1H), 8.47-8.54 (m, 3H), 8.91 (d, (ES⁺), at 3.63 J= 1.2, 1H), 9.05 (d, J = 5.2, min, 100% 1H), 9.45 (dd, J = 7.2, 1.4, 2H)7 3-methyl-5-[6-(1H-pyrazol-1- 26, 34 3 (400 MHz, DMSO-d₆ + D₂O) δ: ppmm/z 262.2 yl)pyrimidin-4-yl]benzonitrile 2.47 (s, 3H), 6.71 (dd, J =2.7, (M + H)⁺ (ES⁺), at 1.5, 1H), 7.86 (s, 1H), 8.00 (d, J = 4.01 min,100% 1.2, 1H), 8.39 (s, 1H), 8.42-8.50 (m, 2H) 8.75 (d, J = 2.4, 1H),9.15 (d, J = 0.9, 1H) 8 3-chloro-5-[6-(1H-pyrazol-1- 20, 34 3 (400 MHz,DMSO-d₆) δ: ppm 6.74 m/z not observed yl)pyrimidin-4-yl]benzonitrile(dd, J = 2.7, 1.5, 1H), 8.04-8.06 (ES⁺), at 4.27 (m, 1H), 8.30 (dd, J =2.0, 1.4, min, 100% 1H), 8.60-8.67 (m, 2H), 8.76-8.80 (m, 2H), 9.21 (d,J = 1.2, 1H) 9 3-chloro-4-fluoro-5-[6-(1H- 17, 34 3 (400 MHz, DMSO-d₆) δppm 6.71 (s, m/z not observed pyrazol-1-yl)pyrimidin-4- 1H), 8.00 (s,1H), 8.36 (s, 1H), (ES⁺), at 4.21 yl]benzonitrile 8.48 (s, 1H), 8.49 (s,1H), 8.74-8.79 min, 100% (m, 1H), 9.23 (s, 1H) 103-chloro-4-fluoro-5-[4-(1H- 17, 35 3 (400 MHz, DMSO-d₆) δ ppm 6.68 m/z299.1, 301.0 pyrazol-1-yl)pyridin-2- (s, 1H), 7.90 (s, 1H), 7.98 (d,(M + H)⁺ (ES⁺), at yl]benzonitrile J = 3.5, 1H), 8.32 (s, 1H), 8.38 3.93min, 100% (dd, J = 10.2, 6.2, 2H), 8.76-8.83 (m, 2H) 113-chloro-4-fluoro-5-[2-(1H-pyrazol- 17, 36 3 (400 MHz, DMSO-d₆ δ ppm6.68 (s, m/z 299.0, 301.1 1-yl)pyridin-4-yl]benzonitrile 1H), 7.90 (s,1H), 7.94-8.01 (m, (M+H)⁺ (ES⁺), at 1H), 8.32 (s, 1H), 8.37 (dd, J =3.93 min, 100% 10.2, 6.6, 2H), 8.75-8.83 (m, 2H) 123-chloro-4-fluoro-5-[6-(4-fluoro- 12, 17 3 (400 MHz, CDCl₃) δ: ppm 7.72(d, m/z not observed 1H-pyrazol-1-yl)pyrimidin-4- J = 4.3, 1H), 7.86(dd, (ES⁺), at 4.59 yl]benzonitrile J = 6.2, 2.0, 1H), 8.43-8.49 min,100% (m, 3H), 9.07-9.11 (m, 1H) 13 3-methyl-5-{6-[(²H₃)-1H-pyrazol- 10,21 3 (400 MHz, CDCl₃) δ: ppm 2.52 m/z 265.31-yl]pyrimidin-4-yl}benzonitrile (s, 3H), 7.62 (s, 1H), 8.21 (M + H)⁺(ES⁺), at (s, 1H), 8.30-8.35 (m, 2H), 3.99 min, 100% 9.06-9.09 (m, 1H)14 3-chloro-5-{6-[(²H₃)-1H-pyrazol-1- 10, 19 3 (400 MHz, CDCl₃) δ: ppm7.79 m/z not observed yl]pyrimidin-4-yl}benzonitrile (s, 1H), 8.35 (d, J= 0.8, (ES⁺), at 4.25 min, 98% 1H), 8.39-8.43 (m, 2H), 9.07-9.11 (m, 1H)15 3-chloro-4-fluoro-5-{6-[(²H₃)-1H- 10,17  3 (400 MHz, CDCl₃) δ: ppm7.86 m/z not observed pyrazol-1-yl]pyrimidin-4- (dd, J = 6.2, 2.0, 1H),(ES⁺), at 4.18 yl}benzonitrile 8.34-8.49 (m, 2H), 9.11 (d, min, 100% J =1.2, 1H) 16 3-(fluoromethyl)-5-[6-(1H-pyrazol- 28, 34 3 (400 MHz,DMSO-d₆) δ: ppm m/z 280.1 1-yl)pyrimidin-4-yl]benzonitrile 5.63 (d, J =47, 2H), 6.74 (M + H)⁺ (ES⁺), at (dd, J = 2.7, 1.8, 1H), 8.04 3.77 min,100% (dd, J = 1.5, 0.6, 1H), 8.13 (d, J = 1.5, 1H), 8.57 (d, J = 1.2,1H), 8.67 (d, J = 1.5, 1H), 8.79 (td, J = 2.7, 1.1, 2H), 9.21 (d, J =1.2, 1H) 17 3-chloro-5-[6-(5-fluoropyridin-2-yl) 18, 30 4 or 5 (400 MHz,DMSO-d₆) δ: ppm 8.02 m/z not observed pyrimidin-4-yl]benzonitrile (td, J= 8.7, 2.7, 1H) (ES⁺), at 4.72 8.29 (dd, J = 2.0, 1.4, 1H) min, 100%8.57-8.67 (m, 2H) 8.76 (t, J = 1.5, 1H) 8.84 (d, J = 2.7, 1H) 8.95 (d, J= 1.5, 1H) 9.44 (d, J = 1.2, 1H) 185-[6-(5-fluoropyridin-2-yl)pyrimidin- 24, 30 4 (400 MHz, DMSO-d₆) δ: ppm8.03 m/z not observed 4-yl]benzene-1,3-dicarbonitrile (td, J = 8.7, 2.7,1H) 8.60 (ES⁺), at 3.95 (dd, J = 8.9, 4.6, 1H) 8.69 min, 100% (t, J =1.4, 1H) 8.85 (d, J = 2.7, 1H) 9.01-9.14 (m, 3H) 9.47 (d, J = 1.2, 1H)19 3-chloro-5-[6-(5-methylpyridin-2- 18, 31 4 (400 MHz, DMSO-d₆) δ: ppm2.44 m/z not observed yl)pyrimidin-4-yl]benzonitrile (s, 3H) 7.87-7.92(m, 1H) 8.27-8.30 (ES⁺), at 4.77 (m, 1H) 8.42 (d, J = 7.9, 1H) min, 100%8.63-8.69 (m, 2H) 8.75 (t, J = 1.4, 1H) 8.96 (d, J = 1.2, 1H) 9.41 (d, J= 1.2, 1H) 20 3-chloro-5-[6-(5-chloropyridin-2- 18, 32 4 (400 MHz,DMSO-d₆) δ: 8.23 (dd, m/z not observed yl)pyrimidin-4-yl]benzonitrile J= 8.5, 2.7, 1H) 8.28-8.32 (ES⁺), at 5.21 (m, 1H) 8.52 (d, J = 8.5, 1H)min, 100% 8.65 (t, J = 1.7, 1H) 8.76 (t, J = 1.5, 1H) 8.88 (d, J = 2.1,1H) 8.97 (d, J = 1.2, 1H) 9.45 (d, J = 1.2, 1H) 215-[6-(pyridin-2-yl)pyrimidin-4-  3, 24 4 (400 MHz, DMSO-d₆) δ: ppm 7.67m/z not observed yl]benzene-1,3-dicarbonitrile (ddd, J = 7.6, 4.8, 1.1,1H) (ES⁺), at 3.57 8.10 (td, J = 7.7, 1.7, 1H) min, 98% 8.53 (d, J =7.9, 1H) 8.69 (t, J = 1.4, 1H) 8.85 (d, J = 4.0, 1H) 9.08 (d, J = 1.5,3H) 9.47 (d, J = 1.2, 1H) 22 3-chloro-4-fluoro-5-[6-(5-fluoropyridin-16, 30 4 (400 MHz, DMSO-d₆) δ: ppm 8.03 m/z not observed2-yl)pyrimidin-4-yl]benzonitrile (td, J = 8.7, 3.1, 1H) 8.51-8.56 (ES⁺),at 4.72 (m, 2H) 8.62 (dd, J = 8.9, 4.6, min, 98% 1H) 8.80 (s, 1H) 8.84(d, J = 3.1, 1H) 9.50 (d, J = 1.2, 1H) 233-methyl-5-[6-(5-methylpyridin-2- 21,33  4 (400 MHz, CDCl₃) δ: ppm 2.49(s, m/z 287.3 yl)pyrimidin-4-yl]benzonitrile 3H), 2.55 (s, 3H), 7.63 (d,J = 0.6, (M + H)⁺ (ES⁺), at 1H), 7.74 (dd, J = 8.1, 1.7, 1H), 4.46 min,100% 8.30 (d, J = 0.6, 1H), 8.37 (s, 1H), 8.47 (d, J = 7.9, 1H), 8.62(d, J = 2.1, 1H), 8.81 (d, J = 1.2, 1H), 9.35 (d, J = 1.5, 1H) 243-[6-(5-fluoropyridin-2-yl)pyrimidin- 30, 39 4 (400 MHz, DMSO-d₆) δ: ppm3.38 (s, m/z 321.1 4-yl]-5-(methoxymethyl)benzonitrile 3H), 4.60 (s,2H), 7.97-8.03 (m, 2H), (M + H)⁺ (ES⁺), at 8.54-8.60 (m, 2H), 8.66 (t, J= 1.6, 3.93 min, 100% 1H), 8.83 (d, J = 2.7, 1H), 8.89 (d, J = 1.2, 1H),9.41 (d, J = 1.2, 1H) 25 3-[6-(5-fluoropyridin-2-yl)pyrimidin- 30, 41 4(400 MHz, DMSO-d₆) δ: ppm 3.94 (s, m/z 307.2 4-yl]-5-methoxybenzonitrile3H), 7.67 (dd, J = 2.5, 1.4, 1H), (M + H)⁺ (ES⁺), at 8.00 (td, J = 8.7,2.9 Hz, 1H), 4.08 min, 100% 8.10 (dd, J = 2.3, 1.6, 1H), 8.31-8.32 (m,1H), 8.58 (dd, J = 9.0, 4.7, 1H), 8.82 (d, J = 2.7, 1H), 8.88 (d, J =1.2, 1H), 9.40 (d, J = 1.6, 1H)

Biological Methods Membrane Preparation

cDNA encoding the human mGlu5 receptor was transfected into HEK293 cellsusing the transfection reagent Genejuice (Novagen). Forty-eight hoursafter transfection, cells were harvested and washed twice with ice coldphosphate-buffered saline. The pellet was re-suspended in ice-coldbuffer containing 20 mM Tris-HCl, pH 7.4, 1 mM EDTA and homogenised withan Ultraturax for 30 s at maximum speed. The suspension was centrifuged(800×g for 5 min at 4° C.) and supernatant collected. Supernatant wascentrifuged (40,000×g for 30 min at 4° C.). The resulting pellet wasre-suspended and frozen at −80° C. before use. Protein concentration wasdetermined using the BCA protein assay method (Merck Chemicals Ltd).

[³H]-M-MPEP Radioligand Binding Assay

After thawing, membrane homogenates were re-suspended in the bindingbuffer (50 mM HEPES pH 7.5, 150 mM NaCl) to a final assay concentrationof 2.5 μg protein per well. Saturation isotherms were determined by theaddition of various concentrations (0-50 nM) of [³H]-M-MPEP (Gaspariniet al. Bioorg. Med. Chem. Lett. 2002, 12, 407-409) in a total reactionvolume of 250 μL for 90 min at rt. At the end of the incubation,membranes were filtered onto a 96-well GF/B filter pre-incubated with0.1% polyethylenimine, with a Tomtec cell harvester and washed 5 timeswith 0.5 mL distilled water. Non-specific binding (NSB) was measured inthe presence of 0.1 mM MPEP hydrochloride (Tocris bioscience, cataloguenumber 1212). Radioactivity on the filter was counted (1 min) on amicrobeta counter after addition of 50 μL of scintillation fluid. Forcompetition binding experiments, membranes were incubated with[³H]-M-MPEP at a concentration equal to the K_(D) value of theradioligand and 10 concentrations of the inhibitory compound (typicallybetween the ranges of 0.1 mM-3.16 pM). IC₅₀ values were derived from theinhibition curve and the equilibrium dissociation constant (K_(i))values were calculated using the Cheng-Prussoff equation. The pK_(i)values (where pK_(i)=−log₁₀ K_(i)) of certain compounds of the inventionare tabulated below.

IPone Accumulation Assay

An inducible human mGlu5 receptor HEK293 stable cell line was used withthe IPone HTRF assay kit (CisBio). The assay was optimised to measurethe ability (potency; pIC₅₀) of antagonists/negative allostericmodulators to reduce agonist (L-quisqualic acid)-induced inositolphosphate turnover. Briefly, cells were plated onto half area 96-wellwhite walled plates at a density of 35,000 cells/well. Sixteen hourspost-plating cell growth media was replaced with 25 μL IPone stimulationbuffer (supplied in the kit) supplemented with 5 mM sodium pyruvate and20 μg/mL glutamate pyruvate transaminase. Cells were incubated in ahumidified atmosphere for 45 min at 37° C. prior to addition of 5 μLcompound for analysis. After a further 15 min incubation time at 37° C.,5 μL of an EC₅₀ concentration (30 μM) of L-quisqualic acid (Tocriscatalogue number 0188) was added to stimulate inositol phosphateturnover. After 30 min of L-quisqualic acid stimulation the assay wasterminated by the addition of detection mixture as per manufacturer'sinstructions. The concentration of compound which reducedL-quisqualic-stimulated turnover of inositol phosphates by 50% (IC₅₀)was calculated. The pIC₅₀ values (where pIC₅₀=−log₁₀ IC₅₀) of certaincompounds of the invention, for instance examples 2, 17 and 18 werepIC₅₀>8.

Ex Vivo mGlu5 Receptor Occupancy

Sprague Dawley rats (male; 250-300 g) were dosed orally with eithervehicle or examples 2, 17 or 18 (1-10 mg/kg po). Vehicle for example 17was 10% DMAC+10% solutol HS 15+80% (10% HP-β-CD in water); for example 2and 18 vehicle was 10% DMAC+5% solutol HS 15+85% (10% VE-TPGS in water).One hour post-dose, animals were sacrificed and whole brains removed,rinsed and blot dried. A coronal block was cut containing thehippocampus and divided along the mid-line and rapidly frozen inisopentane for sectioning and autoradiography. Coronal half-brainsections were cut 20 μm thick, approximately 4 mm posterior to thebregma, to incorporate the hippocampal CA3 region. Three adjacentsections were mounted onto slides and incubated with 2 nM [³H]-M-MPEP(total binding) or 2 nM [³H]-M-MPEP and 10 μM fenobam (non-specificbinding, Tocris bioscience, catalogue number 2386) for 10 min at roomtemperature. Binding was terminated by aspiration and washing withice-cold assay buffer (4×5 min) and sections allowed to air dry. Levelsof bound radioactivity in the sections were determined using a betaimager over a 16 h period. Occupancy was determined as mean specificbinding with the vehicle treated control taken as 100%. Certaincompounds of the invention, for instance example 2, example 17 and 18occupied hippocampal mGlu5 receptors in a dose-dependent manner, withestimated ED₅₀ values of 2.8 mg/kg (po), 0.3 mg/kg (po) and 2.9 mg/kg(po) respectively.

In Vivo Efficacy Test—Marble Burying

Example 17 was assessed for activity in a mouse marble burying test.Male CD-1 mice (25-30 g) were dosed with example 17 (1, 3, 10 and 30mg/kg, po; n=15/group) or vehicle (10% Solutol HS15+90% (10% _((w/v))aqueous HPβCD; n=15/group) 30 min prior to the marble burying test.After 30 min mice were placed individually in a cage containing 24 smallglass marbles (diameter ˜10 mm) evenly spaced and arranged in agrid-like fashion across the bedding. Thirty minutes later the animalswere removed from the cages, and the number of marbles buried by atleast two thirds into sawdust were counted and recorded. A one-way ANOVA(analysis of variance) with Dunnett's post-hoc test showed astatistically significant decrease in the number of marbles buried at adose of 10 and 30 mg/kg versus vehicle group.

Ex No. Name Structure pKi avg 1 3-chloro-4-fluoro-5-[6-(pyridin-2-yl)pyrimidin-4- yl]benzonitrile

8.91 2 3-chloro-5-[6-(pyridin-2- yl)pyrimidin-4- yl]benzonitrile

8.52 3 6-[6-(3-chloro-5- cyanophenyl)pyrimidin-4-yl]pyridine-3-carbonitrile

9.16 4 3-methyl-5-[6-(pyridin-2- yl)pyrimidin-4- yl]benzonitrile

8.56 5 3-chloro-5-[6-(pyridazin-3- yl)pyrimidin-4- yl]benzonitrile

8.01 6 3-(4,4′-bipyrimidin-6-yl)-5- chlorobenzonitrile

8.27 7 3-methyl-5-[6-(1H-pyrazol- 1-yl)pyrimidin-4- yl]benzonitrile

8.39 8 3-chloro-5-[6-(1H-pyrazol- 1-yl)pyrimidin-4- yl]benzonitrile

8.40 9 3-chloro-4-fluoro-5-[6-(1H- pyrazol-1-yl)pyrimidin-4-yl]benzonitrile

9.30 10 3-chloro-4-fluoro-5-[4-(1H- pyrazol-1-yl)pyridin-2-yl]benzonitrile

8.37 11 3-chloro-4-fluoro-5-[2-(1H- pyrazol-1-yl)pyridin-4-yl]benzonitrile

8.16 12 3-chloro-4-fluoro-5-[6-(4- fluoro-1H-pyrazol-1- yl)pyrimidin-4-yl]benzonitrile

8.00 13 3-methyl-5-{6-[(²H₃)-1H- pyrazol-1-yl]pyrimidin-4-yl}benzonitrile

8.24 14 3-chloro-5-{6-[(²H₃)-1H- pyrazol-1-yl]pyrimidin-4-yl}benzonitrile

8.56 15 3-chloro-4-fluoro-5-{6- [(²H₃)-1H-pyrazol-1- yl]pyrimidin-4-yl}benzonitrile

9.08 16 3-(fluoromethyl)-5-[6-(1H- pyrazol-1-yl)pyrimidin-4-yl]benzonitrile

8.17 17 3-chloro-5-[6-(5- fluoropyridin-2- yl)pyrimidin-4-yl]benzonitrile

9.27 18 5-[6-(5-fluoropyridin-2- yl)pyrimidin-4-yl]benzene-1,3-dicarbonitrile

8.78 19 3-chloro-5-[6-(5- methylpyridin-2- yl)pyrimidin-4-yl]benzonitrile

8.61 20 3-chloro-5-[6-(5- chloropyridin-2- yl)pyrimidin-4-yl]benzonitrile

8.77 21 5-[6-(pyridin-2- yl)pyrimidin-4-yl]benzene- 1,3-dicarbonitrile

7.98 22 3-chloro-4-fluoro-5-[6-(5- fluoropyridin-2- yl)pyrimidin-4-yl]benzonitrile

9.05 23 3-methyl-5-[6-(5- methylpyridin-2- yl)pyrimidin-4-yl]benzonitrile

8.67 24 3-[6-(5-fluoropyridin-2- yl)pyrimidin-4-yl]-5-(methoxymethyl)benzonitrile

8.57 25 3-[6-[5-fluoropyridin-2- yl)pyrimidin-4-yl]-5-methoxybenzonitrile

8.37

1-11. (canceled)
 12. A method for the treatment of a substance-relateddisorder comprising administering an effective amount of a compound offormula 2 or a pharmaceutically acceptable salt thereof to a subject inneed thereof:

wherein R₁ is halogen, optionally substituted C₁-C₃ alkyl, cyclopropyl,optionally substituted C₁-C₃ alkoxy, cyano, hydroxyl, nitro or NH₂; R₂is H or F; and Q is an optionally substituted pyridyl or pyrazyl group.13. The method according to claim 12, wherein the substance-relateddisorder is selected from the group consisting of addiction, alcoholabuse, alcohol dependence, alcohol withdrawal, amphetamine dependence,amphetamine withdrawal, cocaine dependence, cocaine withdrawal, opioiddependence, opioid withdrawal, and combinations thereof.
 14. The methodaccording to claim 12, wherein the substance-related disorder is cocainedependence, cocaine withdrawal, or a combination thereof.
 15. The methodaccording to claim 12, wherein the substance-related disorder is alcoholabuse, alcohol dependence, alcohol withdrawal, or combinations thereof.16. The method according to claim 12, wherein the compound is a compoundof formula 3:

or a pharmaceutically acceptable salt thereof, wherein R₁ is halogen,optionally substituted C₁-C₃ alkyl, cyclopropyl, optionally substitutedC₁-C₃ alkoxy, cyano, hydroxyl, nitro or NH₂; R₂ is H or F; R₃ is H,halogen, optionally substituted C₁-C₃ alkyl, optionally substitutedC₁-C₃ alkoxy or cyano; and R₄ is H, halogen, optionally substitutedC₁-C₃ alkyl, optionally substituted C₁-C₃ alkoxy or cyano; and n is 0-3.17. The method according to claim 12, wherein the compound is a compoundof formula 4:

or a pharmaceutically acceptable salt thereof, wherein R₁ is halogen,optionally substituted C₁-C₃ alkyl, cyclopropyl, optionally substitutedC₁-C₃ alkoxy, cyano, hydroxyl, nitro or NH₂; R₂ is H or F; and R₃ is H,halogen, optionally substituted C₁-C₃ alkyl, optionally substitutedC₁-C₃ alkoxy or cyano.
 18. The method according to claim 12, wherein thecompound is a compound of formula 5:

or a pharmaceutically acceptable salt thereof, wherein R₁ is halogen,optionally substituted C₁-C₃ alkyl, cyclopropyl, optionally substitutedC₁-C₃ alkoxy, cyano, hydroxyl, nitro or NH₂; R₂ is H or F; R₅ is H, D,halogen, optionally substituted C₁-C₃ alkyl or cyano; and R₆ is H, D,halogen, optionally substituted C₁-C₃ alkyl or cyano.
 19. The methodaccording to claim 12, wherein R₁ is F, Cl, OMe, CH₂OMe, Me,fluoromethyl or cyano.
 20. The method according to claim 12, wherein R₁is F, Cl or cyano.
 21. The method according to claim 16, wherein R₃ isH, Me, F, Cl or cyano.
 22. The method according to claim 16, wherein nis 0 or
 1. 23. The method according to claim 18, wherein R₅ and R₆ areindependently H, D or F.
 24. The method according to claim 12, whereinthe compound is selected from the group consisting of:3-chloro-4-fluoro-5-[6-(pyridin-2-yl)pyrimidin-4-yl]benzonitrile;3-chloro-5-[6-(pyridin-2-yl)pyrimidin-4-yl]benzonitrile;6-[6-(3-chloro-5-cyanophenyl)pyrimidin-4-yl]pyridine-3-carbonitrile;3-methyl-5-[6-(pyridin-2-yl)pyrimidin-4-yl]benzonitrile;3-methyl-5-[6-(1H-pyrazol-1-yl)pyrimidin-4-yl]benzonitrile;3-chloro-5-[6-(1H-pyrazol-1-yl)pyrimidin-4-yl]benzonitrile;3-chloro-4-fluoro-5-[6-(1H-pyrazol-1-yl)pyrimidin-4-yl]benzonitrile;3-chloro-4-fluoro-5-[4-(1H-pyrazol-1-yl)pyridin-2-yl]benzonitrile;3-chloro-4-fluoro-5-[2-(1H-pyrazol-1-yl)pyridin-4-yl]benzonitrile;3-chloro-4-fluoro-5-[6-(4-fluoro-1H-pyrazol-1-yl)pyrimidin-4-yl]benzonitrile;3-methyl-5-{6-[(²H₃)-1H-pyrazol-1-yl]pyrimidin-4-yl}benzonitrile;3-chloro-5-{6-[(²H₃)-1H-pyrazol-1-yl]pyrimidin-4-yl}benzonitrile;3-chloro-4-fluoro-5-{6-[(²H₃)-1H-pyrazol-1-yl]pyrimidin-4-yl}benzonitrile;3-(fluoromethyl)-5-[6-(1H-pyrazol-1-yl)pyrimidin-4-yl]benzonitrile;3-chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile;5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzene-1,3-dicarbonitrile;3-chloro-5-[6-(5-methylpyridin-2-yl)pyrimidin-4-yl]benzonitrile;3-chloro-5-[6-(5-chloropyridin-2-yl)pyrimidin-4-yl]benzonitrile;5-[6-(pyridin-2-yl)pyrimidin-4-yl]benzene-1,3-dicarbonitrile;3-chloro-4-fluoro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile;3-methyl-5-[6-(5-methylpyridin-2-yl)pyrimidin-4-yl]benzonitrile;3-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]-5-(methoxymethyl)benzonitrile;3-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]-5-methoxybenzonitrile; andpharmaceutically acceptable salts thereof.
 25. The method according toclaim 24, wherein the substance-related disorder is selected from thegroup consisting of addiction, alcohol abuse, alcohol dependence,alcohol withdrawal, amphetamine dependence, amphetamine withdrawal,cocaine dependence, cocaine withdrawal, opioid dependence, opioidwithdrawal, and combinations thereof.
 26. The method according to claim24, wherein the substance-related disorder is cocaine dependence,cocaine withdrawal, or a combination thereof.
 27. The method accordingto claim 24, wherein the substance-related disorder is alcohol abuse,alcohol dependence, alcohol withdrawal, or combinations thereof.
 28. Themethod according to claim 12, wherein the compound is3-chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile.
 29. Themethod according to claim 28, wherein the substance-related disorder isselected from the group consisting of addiction, alcohol abuse, alcoholdependence, alcohol withdrawal, amphetamine dependence, amphetaminewithdrawal, cocaine dependence, cocaine withdrawal, opioid dependence,opioid withdrawal, and combinations thereof.
 30. The method according toclaim 28, wherein the substance-related disorder is cocaine dependence,cocaine withdrawal, or a combination thereof.
 31. The method accordingto claim 28, wherein the substance-related disorder is alcohol abuse,alcohol dependence, alcohol withdrawal, or combinations thereof.
 32. Themethod according to claim 12, wherein the compound is selected from thegroup consisting of:3-methyl-5-[6-(1H-pyrazol-1-yl)pyrimidin-4-yl]benzonitrile;3-chloro-5-[6-(1H-pyrazol-1-yl)pyrimidin-4-yl]benzonitrile;3-chloro-4-fluoro-5-[6-(1H-pyrazol-1-yl)pyrimidin-4-yl]benzonitrile;3-chloro-4-fluoro-5-[4-(1H-pyrazol-1-yl)pyridin-2-yl]benzonitrile;3-chloro-4-fluoro-5-[2-(1H-pyrazol-1-yl)pyridin-4-yl]benzonitrile;3-chloro-4-fluoro-5-[6-(4-fluoro-1H-pyrazol-1-yl)pyrimidin-4-yl]benzonitrile;3-methyl-5-{6-[(²H₃)-1H-pyrazol-1-yl]pyrimidin-4-yl}benzonitrile;3-chloro-5-{6-[(²H₃)-1H-pyrazol-1-yl]pyrimidin-4-yl}benzonitrile;3-chloro-4-fluoro-5-{6-[(²H₃)-1H-pyrazol-1-yl]pyrimidin-4-yl}benzonitrile;3-(fluoromethyl)-5-[6-(1H-pyrazol-1-yl)pyrimidin-4-yl]benzonitrile; andpharmaceutically acceptable salts thereof.
 33. The method according toclaim 32, wherein the substance-related disorder is selected from thegroup consisting of addiction, alcohol abuse, alcohol dependence,alcohol withdrawal, amphetamine dependence, amphetamine withdrawal,cocaine dependence, cocaine withdrawal, opioid dependence, opioidwithdrawal, and combinations thereof.